754 results
Search Results
2. Viral hepatitis-induced acute liver failure.
- Author
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Biswas S, Kumar R, Shalimar, and Acharya SK
- Subjects
- Humans, Diagnosis, Differential, Plasma Exchange, Liver Failure, Acute etiology, Liver Failure, Acute therapy, Hepatitis, Viral, Human, Liver Transplantation, Antiviral Agents therapeutic use
- Abstract
Viral hepatitis-induced acute liver failure (ALF) is a preventable cause for liver-related mortality worldwide. Viruses are the most common cause for ALF in developing nations in contrast to the west, where acetaminophen is largely responsible. Viruses may be hepatotropic or affect the liver secondary to a systemic infection. In tropical countries, infections such as leptospirosis, scrub typhus and malaria can mimic the symptoms of ALF. Differentiating these ALF mimics is crucial because they require etiology-specific therapy. Treatment of viral hepatitis-induced ALF is two-pronged and directed towards providing supportive care to prevent organ failures and antiviral drugs for some viruses. Liver transplantation (LT) is an effective modality for patients deteriorating despite adequate supportive care. Early referral and correct identification of patients who require a transplant are important. Liver support devices and plasma exchange have evolved into "bridging modalities" for LT. Preventive strategies such as hand hygiene, use of clean and potable water and inclusion of vaccines against viral hepatitis in the national program are simple yet very effective methods focusing on the preventive aspect of this disease., (© 2024. Indian Society of Gastroenterology.)
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- 2024
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3. Two years into COVID-19 - Lessons in SARS-CoV-2 and a perspective from papers in FEBS Letters
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Urs F. Greber
- Subjects
medicine.medical_specialty ,History ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Biophysics ,Disease ,medicine.disease_cause ,Virus Replication ,Biochemistry ,Antiviral Agents ,Patient care ,03 medical and health sciences ,0302 clinical medicine ,Structural Biology ,Pandemic ,Genetics ,medicine ,Animals ,Humans ,China ,Molecular Biology ,030304 developmental biology ,Coronavirus ,0303 health sciences ,SARS-CoV-2 ,Outbreak ,COVID-19 ,Cell Biology ,3. Good health ,COVID-19 Drug Treatment ,Family medicine ,Commentary ,030217 neurology & neurosurgery - Abstract
The 2019 outbreak of coronavirus disease (COVID-19) in Wuhan (Hubei province of China) has given rise to a pandemic spread of virus, more than 240 million incidences and a death toll larger than 5 million people. COVID-19 has set off large efforts in research, therapy and patient care, as well as public and private debates in every imaginable form. A number of scientists used the publication platforms provided by the Federation of the European Biochemical Societies (FEBS) to present their research data, reviews, opinions and other contributions relating to COVID-19 and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, I highlight the recent COVID-19 papers which have been published and collected in a Virtual Issue in FEBS Letters, and discuss their implications towards understanding the molecular, biochemical and cellular mechanisms of SARS-CoV-2 infections, vaccine development and antiviral discovery strategies.
- Published
- 2021
4. Pharmacological treatment of COVID-19: an opinion paper
- Author
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Alberto García-Lledó, Javier Gómez-Pavón, Juan González del Castillo, Teresa Hernández-Sampelayo, Mari Cruz Martín-Delgado, Francisco Javier Martín Sánchez, Manuel Martínez-Sellés, José María Molero García, Santiago Moreno Guillén, Fernando Rodríguez-Artalejo, Julián Ruiz-Galiana, Rafael Cantón, Pilar De Lucas Ramos, Alejandra García-Botella, and Emilio Bouza
- Subjects
Microbiology (medical) ,Pharmacology ,SARS-CoV-2 ,Humans ,General Medicine ,Antiviral Agents ,Pandemics ,COVID-19 Drug Treatment - Abstract
The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation. pre-print 258 KB
- Published
- 2021
5. A pan-serotype dengue virus inhibitor targeting the NS3-NS4B interaction.
- Author
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Kaptein SJF, Goethals O, Kiemel D, Marchand A, Kesteleyn B, Bonfanti JF, Bardiot D, Stoops B, Jonckers THM, Dallmeier K, Geluykens P, Thys K, Crabbe M, Chatel-Chaix L, Münster M, Querat G, Touret F, de Lamballerie X, Raboisson P, Simmen K, Chaltin P, Bartenschlager R, Van Loock M, and Neyts J
- Subjects
- Animals, Antiviral Agents pharmacokinetics, Antiviral Agents therapeutic use, Dengue drug therapy, Dengue Virus genetics, Dengue Virus metabolism, Disease Models, Animal, Female, Male, Membrane Proteins antagonists & inhibitors, Mice, RNA Helicases antagonists & inhibitors, RNA Helicases metabolism, Serine Endopeptidases metabolism, Viral Load drug effects, Viral Nonstructural Proteins antagonists & inhibitors, Viremia drug therapy, Viremia virology, Virus Replication drug effects, Antiviral Agents pharmacology, Dengue virology, Dengue Virus classification, Dengue Virus drug effects, Membrane Proteins metabolism, Viral Nonstructural Proteins metabolism
- Abstract
Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue
1,2 . There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action. JNJ-A07 has a favourable pharmacokinetic profile that results in outstanding efficacy against dengue virus infection in mouse infection models. Delaying start of treatment until peak viraemia results in a rapid and significant reduction in viral load. An analogue is currently in further development., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)- Published
- 2021
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6. Current strategies in diagnostics and therapeutics against novel coronavirus disease (COVID-19).
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Alotaibi F
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- Humans, SARS-CoV-2, COVID-19 Testing, Antiviral Agents therapeutic use, COVID-19 diagnosis
- Abstract
The epidemic of COVID-19 spread quickly through China and engulfed all of the countries across the globe. Several advances have been made in understanding the novel coronavirus's pathophysiology and in the development of newer diagnostics with pinpoint accuracy. Several newer therapeutic methods have either been accepted or are awaiting acceptance. In many countries, vaccination programs have been rolled out. Despite all these efforts, coronavirus still exists, though with lesser propensity. Multiple new forms of the novel coronavirus unexpectedly appeared in various areas of the world, undermining previously existing diagnosis and care protocols. This article highlights our understanding of the novel coronavirus's symptoms in brief, pathogenesis, diagnostics, and therapeutic strategies to contain COVID-19. The clinical findings, including serological, radiological, and other advanced diagnostic strategies, contributed much to control the disease. To date, supportive interventions have been used in tandem with potent antiviral therapies such as remdesivir, lopinavir/ritonavir, or corticosteroids with a level of trust in the care of COVID-19 patients. However, in several areas of the world, vaccination initiatives took place; the vaccines' safety and efficacy to control the outbreak is yet to be identified. This review concludes that improvement in therapies and diagnostics for COVID-19 must continually be explored as new variants constantly emerge., (© 2022 Faisal Alotaibi., published by Sciendo.)
- Published
- 2021
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7. Brief Report: HCV Universal Test-and-Treat With Direct Acting Antivirals for Prisoners With or Without HIV: A Prison Health Care Workers-Led Model for HCV Microelimination in Thailand.
- Author
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Supanan R, Han WM, Harnpariphan W, Ueaphongsukkit T, Ubolyam S, Sophonphan J, Tangkijvanich P, Thanprasertsuk S, and Avihingsanon A
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- Adult, Continuity of Patient Care, Female, HIV Infections complications, HIV Infections drug therapy, HIV Infections epidemiology, Health Personnel, Hepacivirus genetics, Hepatitis C diagnosis, Hepatitis C drug therapy, Hepatitis C, Chronic diagnosis, Hepatitis C, Chronic epidemiology, Humans, Male, Middle Aged, Sustained Virologic Response, Thailand epidemiology, Treatment Outcome, Antiviral Agents therapeutic use, Hepacivirus isolation & purification, Hepatitis C, Chronic drug therapy, Mass Screening methods, Prisoners, Prisons
- Abstract
Background: This study investigated the sustained virologic responses (SVRs) among prisoners with hepatitis C virus (HCV) using universal test-and-treat approach by prison health care workers in a central male prison in Thailand., Methods: A universal HCV screening was conducted in a maximum-security central prison (Klong Prem Central Prison) in Thailand. HCV RNA-confirmed prisoners were treated with generic sofosbuvir/velpatasvir by prison health care workers, regardless of their HCV genotypes and duration of prison sentences. We evaluated the SVR rates at 12 weeks after completing direct acting antivirals (DAA) treatment., Results: A total of 68 prisoners with detectable HCV RNA received DAA treatment. The median age and duration of prison sentences were 44 years (interquartile range, 41-53) and 25 (interquartile range, 19-33) years, respectively. Twenty-five percentage of the participants was coinfected with HIV, and 6% of the participants was coinfected with hepatitis B virus. Among all prisoners who received DAA treatment, 20 (29%) had genotype (GT)-1a, 3 (4%) had GT-1b, 22 (32%) had GT-3a, 3 (4%) had GT-3b, and 7 (10%) had GT-6. Overall, improvements in liver biomarkers were seen after HCV treatment, and SVR was achieved in 97% of the participants with per-protocol analysis and in 90% of the participants with intention-to-treat analysis., Conclusions: HCV treatment using DAA among prisoners through universal test-and-treat approach led by prison health care workers is highly effective and safe, and such model can potentially help to facilitate the goals of HCV microelimination among prisoners in Thailand., Competing Interests: P.T. received funding from The Thailand Research Fund (TRF) Senior Research Scholar (RTA6280004), Center of Excellence in Hepatitis and Liver Cancer, Faculty of Medicine, Chulalongkorn University. T.U. is supported by Second Century Fund (C2F), Chulalongkorn University. The remaining authors have no conflicts of interest to disclose., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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8. Risk assessment of therapeutic agents under consideration to treat COVID-19 in paediatric patients and pregnant women.
- Author
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Barrett JS
- Subjects
- Antiviral Agents adverse effects, Child, Clinical Trials as Topic, Drug Combinations, Female, Humans, Pandemics, Pregnancy, Pregnant Women, Prospective Studies, Risk Assessment, Antiviral Agents therapeutic use, COVID-19 Drug Treatment
- Abstract
Aim: Repurposing strategies to address the COVID-19 pandemic have been accelerated. As both pregnant and paediatric patients are likely to be excluded from most planned investigations, the list of repurposed options and the available data on these drugs and vaccines provide a baseline risk assessment and identify gaps for targeted investigation., Methods: Clinical trials have been searched and reviewed; 23 repurposed drugs and drug combinations and nine candidate vaccines have been assessed regarding the availability of relevant data in paediatrics and pregnant women and to evaluate expected or unanticipated risk., Results: Thirteen of the repurposed drugs or drug combinations are indicated for use in paediatrics in some age category albeit for indications other than COVID-19; 10 of these are indicated for use in pregnant women. Even in cases where these drugs are indicated in the populations, source data from which safety and or dosing could be extrapolated for use in COVID-19 is sparse. Vaccine trials are ongoing and generally exclude pregnant women; only in a few instances have paediatric subgroups been planned for enrolment. Data from individual case studies and RWD may suggest that subpopulations of both paediatric patients and pregnant women may be more at risk, particularly those in an increased inflammatory state., Conclusion: In conjunction with more prospective collaboration, plans are evolving to ensure that we will be better prepared to address similar situations especially in paediatrics and pregnant women where experience is limited and actual practice relies heavily on leveraging data from other populations and indications., (© 2020 British Pharmacological Society.)
- Published
- 2021
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9. Treatment of children with COVID-19: update of the Italian Society of Pediatric Infectious Diseases position paper.
- Author
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Venturini, Elisabetta, Montagnani, Carlotta, Garazzino, Silvia, Donà, Daniele, Pierantoni, Luca, Lo Vecchio, Andrea, Krzysztofiak, Andrzej, Nicolini, Giangiacomo, Bianchini, Sonia, Galli, Luisa, Villani, Alberto, and Gattinara, Guido Castelli
- Subjects
METHYLPREDNISOLONE ,COVID-19 ,COMMUNICABLE diseases ,DEXAMETHASONE ,PEDIATRICS ,ANTIVIRAL agents ,MONOCLONAL antibodies ,SEVERITY of illness index ,CONVALESCENT plasma ,OXYGEN therapy ,PREDNISONE ,CHILDREN - Published
- 2021
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10. Virucidal and biodegradable specialty cellulose nonwovens as personal protective equipment against COVID-19 pandemic
- Author
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Qiang Yong, Huining Xiao, Ling Zheng, Zhenghong Yuan, Xiangyu Jin, Chao Deng, Farzad Seidi, and Chengcheng Li
- Subjects
Materials science ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,02 engineering and technology ,010402 general chemistry ,Antiviral Agents ,01 natural sciences ,chemistry.chemical_compound ,Face mask ,Nonwoven ,Humans ,Antiviral ,Cellulose ,Pandemics ,Personal Protective Equipment ,Personal protective equipment ,ComputingMethodologies_COMPUTERGRAPHICS ,Multidisciplinary ,SARS-CoV-2 ,COVID-19 ,021001 nanoscience & nanotechnology ,Pulp and paper industry ,Anti-Bacterial Agents ,0104 chemical sciences ,3. Good health ,Antibacterial ,Face masks ,Polyhexamethylene guanidine ,chemistry ,13. Climate action ,Original Article ,0210 nano-technology - Abstract
Graphical abstract, Introduction Face masks are regarded as effective Personal Protective Equipment (PPE) during the COVID-19 pandemic. However, the dominant polypropylene (PP)-based masks are devoid of antiviral/antibacterial activities and create enormous environmental burdens after disposal. Objectives Here we report a facile and potentially scalable method to fabricate biodegradable, breathable, and biocidal cellulose nonwovens (BCNWs) to address both environmental and hygienic problems of commercially available face masks. Methods TEMPO-oxidized cellulose nonwovens are rendered antiviral/antibacterial via covalent bonding with disinfecting polyhexamethylene guanidine or neomycin sulfate through carbodiimide coupling chemistry. Results The obtained results showed that the BCNWs have virucidal rate of >99.14%, bactericidal efficiency of >99.51%, no leaching-out effect, and excellent air permeability of >1111.5 mm s−1. More importantly, the as-prepared BCNWs can inactivate SARS-CoV-2 instantly. Conclusions This strategy provides a new platform for the green fabrication of multifunctional cellulose nonwovens as scalable bio-protective layers with superior performance for various PPE in fighting COVID-19 or future pandemics. Additionally, replacing the non-biodegradable non-antimicrobial PP-based masks with the cellulose-based masks can reduce the plastic wastes and lower the greenhouse gas production from the incineration of disposed masks.
- Published
- 2022
11. HIV and influenza fusion peptide interactions with (dis)ordered lipid bilayers: Understanding mechanisms and implications for antimicrobial and antiviral approaches.
- Author
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Miłogrodzka I, Le Brun AP, Banaszak Holl MM, and van 't Hag L
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- Humans, Orthomyxoviridae drug effects, Orthomyxoviridae metabolism, Quartz Crystal Microbalance Techniques, Lipid Bilayers chemistry, Lipid Bilayers metabolism, HIV Envelope Protein gp41 chemistry, HIV Envelope Protein gp41 metabolism, Antiviral Agents chemistry, Antiviral Agents pharmacology, Antiviral Agents metabolism
- Abstract
The interactions of viral fusion peptides from influenza (E4K and Ac-E4K) and human immunodeficiency virus (gp41 and Ac-gp41) with planar lipid bilayers and monolayers was investigated herein. A combination of surface-sensitive techniques, including quartz crystal microbalance with dissipation (QCM-D), Langmuir-Blodgett area-pressure isotherms with Micro-Brewster angle microscopy, and neutron reflectometry, was employed. Differences in the interactions of the viral fusion peptides with lipid bilayers featuring ordered and disordered phases, as well as lipid rafts, were revealed. The HIV fusion peptide (gp41) exhibited strong binding to the DOPC/DOPS bilayer, comprising a liquid disordered phase, with neutron reflectometry (NR) showing interaction with the bilayer's headgroup area. Conversely, negligible binding was observed with lipid bilayers in a liquid ordered phase. Notably, the influenza peptide (E4K) demonstrated slower binding kinetics with DOPC/DOPS bilayers and distinct interactions compared to gp41, as observed through QCM-D. This suggests different mechanisms of interaction with the lipid bilayers: one peptide interacts more within the headgroup region, while the other is more involved in transmembrane interactions. These findings hold implications for understanding viral fusion mechanisms and developing antimicrobials and antivirals targeting membrane interactions. The differential binding behaviours of the viral fusion peptides underscore the importance of considering membrane composition and properties in therapeutic strategy design., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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12. Identification of new benzofuran derivatives as STING agonists with broad-spectrum antiviral activity.
- Author
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Paulis A, Onali A, Vidalain PO, Lotteau V, Jaquemin C, Corona A, Distinto S, Delogu GL, and Tramontano E
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- Humans, HEK293 Cells, SARS-CoV-2 drug effects, Animals, Molecular Docking Simulation, Interferon-beta genetics, Cell Line, Chlorocebus aethiops, Vero Cells, Benzofurans pharmacology, Benzofurans chemistry, Antiviral Agents pharmacology, Antiviral Agents chemistry, Virus Replication drug effects, Membrane Proteins genetics, Membrane Proteins metabolism
- Abstract
The Stimulator of Interferon Genes (STING) is involved in cytosolic DNA sensing and type I Interferons (IFN-I) induction. Aiming to identify new STING agonists with antiviral activity and given the known biological activity of benzothiazole and benzimidazole derivatives, a series of benzofuran derivatives were tested for their ability to act as STING agonists, induce IFN-I and inhibit viral replication. Compounds were firstly evaluated in a gene reporter assay measuring luciferase activity driven by the human IFN-β promoter in cells expressing exogenous STING (HEK293T). Seven of them were able to induce IFN-β transcription while no induction of the IFN promoter was observed in the presence of a mutated and inactive STING, showing specific protein-ligand interaction. Docking studies were performed to predict their putative binding mode. The best hit compounds were then tested on human coronavirus 229E replication in BEAS-2B and MRC-5 cells and three derivatives showed EC
50 values in the μM range. Such compounds were also tested on SARS-CoV-2 replication in BEAS-2B cells and in Calu-3 showing they can inhibit SARS-CoV-2 replication at nanomolar concentrations. To further confirm their IFN-dependent antiviral activity, compounds were tested to verify their effect on phospho-IRF3 nuclear localization, that was found to be induced by benzofuran derivatives, and SARS-CoV-2 replication in Vero E6 cells, lacking IFN production, founding them to be inactive. In conclusion, we identified benzofurans as STING-dependent immunostimulatory compounds and host-targeting inhibitors of coronaviruses representing a novel chemical scaffold for the development of broad-spectrum antivirals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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13. Antiviral susceptibility of SARS-CoV-2 and influenza viruses from 3 co-infected pediatric patients.
- Author
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Takashita E, Ichikawa M, Fujisaki S, Morita H, Nagata S, Miura H, Watanabe S, Hasegawa H, and Kawaoka Y
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- Humans, Child, Male, Child, Preschool, Influenza A Virus, H1N1 Subtype drug effects, Female, Influenza A Virus, H3N2 Subtype drug effects, Influenza A Virus, H3N2 Subtype genetics, Japan epidemiology, COVID-19 Drug Treatment, Influenza, Human drug therapy, Influenza, Human virology, Antiviral Agents therapeutic use, Antiviral Agents pharmacology, Coinfection virology, Coinfection drug therapy, SARS-CoV-2 drug effects, COVID-19 epidemiology, COVID-19 virology
- Abstract
In Japan, influenza activity was low throughout the COVID-19 pandemic until the 2022-23 season, when the first influenza outbreak occurred since the 2020-21 season. In our influenza surveillance during the COVID-19 pandemic, co-infection with SARS-CoV-2 and influenza virus had not been detected; however, in January 2024, we identified three pediatric outpatients co-infected with these viruses: one with SARS-CoV-2 Omicron EG.5 sublineage HK.3 and influenza A(H3N2) and two with SARS-CoV-2 Omicron BA.2.86 sublineage JN.1.5 and influenza A(H1N1)pdm09. We evaluated the susceptibility of SARS-CoV-2 against RNA-dependent RNA polymerase inhibitors (remdesivir and molnupiravir) and 3C-like protease inhibitors (nirmatrelvir and ensitrelvir), and that of influenza viruses against neuraminidase inhibitors (oseltamivir, peramivir, zanamivir, and laninamivir) and the cap-dependent endonuclease inhibitor baloxavir. All viruses tested were susceptible to these antiviral drugs and did not possess amino acid substitutions associated with reduced antiviral susceptibility. The patients were treated with anti-influenza drugs and did not develop severe symptoms despite the co-infection. Since SARS-CoV-2 and influenza viruses continue to evolve, continuous monitoring of their circulation remains essential to assess public health measures and support clinical management., Competing Interests: Declarations of competing interest Yoshihiro Kawaoka has received collaborative research funds from FUJIFILM Toyama Chemical Co. LTD, Shionogi & Co. LTD, and Daiichi Sankyo Pharmaceutical and is a founder of FluGen. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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14. Utilization of the EpiMed Coronabank Chemical Collection to identify potential SARS-CoV-2 antivirals: in silico studies targeting the nsp14 ExoN domain and PL pro naphthalene binding site.
- Author
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Liang JJ, Pitsillou E, Lau HLY, Mccubbery CP, Gan H, Hung A, and Karagiannis TC
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- Binding Sites, Humans, Exoribonucleases metabolism, Exoribonucleases chemistry, Viral Nonstructural Proteins chemistry, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins metabolism, Viral Nonstructural Proteins genetics, Naphthalenes chemistry, Naphthalenes pharmacology, Protein Binding, COVID-19 Drug Treatment, Small Molecule Libraries chemistry, Small Molecule Libraries pharmacology, Molecular Dynamics Simulation, Protein Domains, Antiviral Agents chemistry, Antiviral Agents pharmacology, Molecular Docking Simulation, SARS-CoV-2 drug effects
- Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome encodes 29 proteins including four structural, 16 nonstructural (nsps), and nine accessory proteins (https://epimedlab.org/sars-cov-2-proteome/). Many of these proteins contain potential targetable sites for the development of antivirals. Despite the widespread use of vaccinations, the emergence of variants necessitates the investigation of new therapeutics and antivirals. Here, the EpiMed Coronabank Chemical Collection (https://epimedlab.org/crl/) was utilized to investigate potential antivirals against the nsp14 exoribonuclease (ExoN) domain. Molecular docking was performed to evaluate the binding characteristics of our chemical library against the nsp14 ExoN site. Based on the initial screen, trisjuglone, ararobinol, corilagin, and naphthofluorescein were identified as potential lead compounds. Molecular dynamics (MD) simulations were subsequently performed, with the results highlighting the stability of the lead compounds in the nsp14 ExoN site. Protein-RNA docking revealed the potential for the lead compounds to disrupt the interaction with RNA when bound to the ExoN site. Moreover, hypericin, cyanidin-3-O-glucoside, and rutin were previously identified as lead compounds targeting the papain-like protease (PL
pro ) naphthalene binding site. Through performing MD simulations, the stability and interactions of lead compounds with PLpro were further examined. Overall, given the critical role of the exonuclease activity of nsp14 in ensuring viral fidelity and the multifunctional role of PLpro in viral pathobiology and replication, these nsps represent important targets for antiviral drug development. Our databases can be utilized for in silico studies, such as the ones performed here, and this approach can be applied to other potentially druggable SARS-CoV-2 protein targets., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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15. Novel quinoline substituted autophagy inhibitors attenuate Zika virus replication in ocular cells.
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Singh S, Ahmad F, Aruri H, Das S, Parajuli P, Gavande NS, Singh PK, and Kumar A
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- Humans, Cell Line, Chlorocebus aethiops, Animals, Vero Cells, Zika Virus drug effects, Zika Virus physiology, Autophagy drug effects, Virus Replication drug effects, Antiviral Agents pharmacology, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Quinolines pharmacology, Quinolines chemistry, Quinolines chemical synthesis, Zika Virus Infection drug therapy, Zika Virus Infection virology
- Abstract
Zika virus (ZIKV) is a re-emerging RNA virus that is known to cause ocular and neurological abnormalities in infants. ZIKV exploits autophagic processes in infected cells to enhance its replication and spread. Thus, autophagy inhibitors have emerged as a potent therapeutic target to combat RNA viruses, with Hydroxychloroquine (HCQ) being one of the most promising candidates. In this study, we synthesized several novel small-molecule quinoline derivatives, assessed their antiviral activity, and determined the underlying molecular mechanisms. Among the nine synthesized analogs, two lead candidates, labeled GL-287 and GL-382, significantly attenuated ZIKV replication in human ocular cells, primarily by inhibiting autophagy. These two compounds surpassed the antiviral efficacy of HCQ and other existing autophagy inhibitors, such as ROC-325, DC661, and GNS561. Moreover, unlike HCQ, these novel analogs did not exhibit cytotoxicity in the ocular cells. Treatment with compounds GL-287 and GL-382 in ZIKV-infected cells increased the abundance of LC3 puncta, indicating the disruption of the autophagic process. Furthermore, compounds GL-287 and GL-382 effectively inhibited the ZIKV-induced innate inflammatory response in ocular cells. Collectively, our study demonstrates the safe and potent antiviral activity of novel autophagy inhibitors against ZIKV., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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16. The effect of oral antiviral therapy for COVID-19 in managing non-hospitalized patients with lung cancer.
- Author
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Hsu WH, Shiau BW, Tsai YW, Wu JY, Huang PY, Chuang MH, Liu TH, Lai CC, and Weng TC
- Subjects
- Humans, Male, Female, Retrospective Studies, Middle Aged, Aged, Administration, Oral, Hospitalization statistics & numerical data, COVID-19 mortality, Hydroxylamines therapeutic use, Hydroxylamines administration & dosage, Treatment Outcome, Drug Combinations, Cytidine analogs & derivatives, Antiviral Agents therapeutic use, Antiviral Agents administration & dosage, Lung Neoplasms drug therapy, Lung Neoplasms mortality, Ritonavir therapeutic use, Ritonavir administration & dosage, COVID-19 Drug Treatment, SARS-CoV-2
- Abstract
Backgrounds: The effectiveness of oral antiviral therapy including nirmatrelvir plus ritonavir and molnupiravir in managing COVID-19 among individuals with pre-existing lung cancer was unclear. Therefore, this study was conducted to evaluate the usefulness of antiviral agents in the management of COVID-19 among patients with lung cancer., Methods: Utilizing data from the TriNetX - a global health research network, a retrospective cohort study was conducted involving 2484 patients diagnosed with both lung cancer and COVID-19. Propensity score matching (PSM) was employed to create well-balanced cohorts. The study assessed the primary outcome of all-cause hospitalization or mortality within a 30-day follow-up., Results: After PSM, the oral antiviral group exhibited a significantly lower risk of the primary composite outcome compared to the control group (6.1 % vs. 9.9 %; HR: 0.60; 95 % CI: 0.45-0.80). This association was consistent across various subgroups according to age, sex, vaccine status, type of oral antiviral agent, and lung cancer characteristics. Additionally, the oral antiviral group showed a lower risk of all-cause hospitalization (HR: 0.73; 95 % CI: 0.54-0.99) and a significantly lower risk of mortality (HR: 0.16; 95 % CI: 0.06-0.41)., Conclusion: The study suggests a favorable impact of oral antiviral therapy on the outcomes of COVID-19 in individuals with lung cancer and support the potential utility of oral antiviral agents in improving outcomes in this vulnerable population., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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17. Early use of oral antiviral drugs and the risk of post COVID-19 syndrome: A systematic review and network meta-analysis.
- Author
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Jiang J, Li Y, Jiang Q, Jiang Y, Qin H, and Li Y
- Subjects
- Humans, Administration, Oral, Drug Combinations, Hydroxylamines therapeutic use, Hydroxylamines administration & dosage, Post-Acute COVID-19 Syndrome, Lactams, Cytidine analogs & derivatives, Nitriles, Proline, Leucine, Antiviral Agents therapeutic use, Antiviral Agents administration & dosage, Ritonavir therapeutic use, Ritonavir administration & dosage, Network Meta-Analysis, COVID-19 Drug Treatment, SARS-CoV-2, COVID-19 epidemiology
- Abstract
Objectives: This study aimed to determine the association of early use of oral antiviral drugs (including nirmatrelvir-ritonavir and molnupiravir) with the risk of post COVID-19 condition (PCC) and compare the possible efficacy of nirmatrelvir-ritonavir and molnupiravir., Methods: PubMed, Web of Science, Embase, Cochrane, MedRxiv, and Psycinfo were searched from inception until November 1, 2023. We included studies that assessed the effect of oral antiviral drugs on the incidence of PCC. Pairwise and network meta-analyses were conducted using a random-effects model. Risk ratios (RRs) for oral antiviral drugs were calculated with a confidence interval (CI)., Results: Nine observational studies containing 866,066 patients were included. Nirmatrelvir-ritonavir and molnupiravir were evaluated in eight and two studies respectively, with both drugs evaluated in one study. Pair-wise meta-analysis showed that early oral antiviral drugs reduced PCC risk (RR 0.77, 95% CI 0.68-0.88). Network meta-analysis showed that nirmatrelvir-ritonavir may perform better than molnupiravir (surface under the cumulative ranking curve: 95.5% vs. 31.6%) at reducing PCC risk., Conclusions: Early use of oral antiviral drugs may potentially protect against developing PCC in non-hospitalized patients with COVID-19. These findings support the standardized administration of oral antiviral drugs in patients during the acute phase of COVID-19 according to the guidelines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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18. Doxycycline inhibits neurotropic enterovirus proliferation in vitro.
- Author
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Chi F, Liu X, Li J, Guo M, Zhang Z, Zhou H, Carr MJ, Li Y, and Shi W
- Subjects
- Humans, Enterovirus Infections virology, Enterovirus Infections drug therapy, Enterovirus A, Human drug effects, Enterovirus A, Human physiology, Cell Line, Enterovirus D, Human drug effects, Enterovirus D, Human physiology, Animals, Virus Internalization drug effects, Doxycycline pharmacology, Virus Replication drug effects, Antiviral Agents pharmacology, Enterovirus drug effects, Enterovirus physiology
- Abstract
Human enteroviruses (EVs) represent a global public health concern due to their association with a range of serious pediatric illnesses. Despite the high morbidity and mortality exerted by EVs, no broad-spectrum antivirals are currently available. Herein, we presented evidence that doxycycline can inhibit in vitro replication of various neurotropic EVs, including enterovirus A71 (EV-A71), enterovirus D68 (EV-D68), and coxsackievirus (CV)-A6, in a dose-dependent manner. Further investigations indicated that the drug primarily acted at the post-entry stage of virus infection in vitro, with inhibitory effects reaching up to 89 % for EV-A71 when administered two hours post-infection. These findings provide valuable insights for the development of antiviral drugs against EV infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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19. Clinical outcomes and safety of remdesivir in hospitalized individuals with COVID-19, with or without severe renal impairment.
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Chang MC, Wu PF, Ho YC, Lin WY, Wu CY, Liu SY, Liu CJ, and Lin YT
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- Humans, Male, Female, Aged, Middle Aged, Treatment Outcome, Aged, 80 and over, Retrospective Studies, Taiwan epidemiology, Glomerular Filtration Rate, Adenosine Monophosphate analogs & derivatives, Adenosine Monophosphate therapeutic use, Adenosine Monophosphate adverse effects, Alanine analogs & derivatives, Alanine therapeutic use, Alanine adverse effects, COVID-19 Drug Treatment, Antiviral Agents therapeutic use, Antiviral Agents adverse effects, Renal Insufficiency, SARS-CoV-2, Hospitalization statistics & numerical data, Acute Kidney Injury chemically induced, Acute Kidney Injury mortality, COVID-19 mortality, COVID-19 complications
- Abstract
Background: The use of remdesivir in patients with coronavirus disease 2019 (COVID-19) and severe renal impairment has been approved; however, limited clinical data exist. Accordingly, we aimed to compare outcomes and adverse events associated with remdesivir in hospitalized patients with COVID-19, with and without severe renal impairment., Methods: Hospitalized patients with COVID-19 undergoing a 5-day remdesivir course at Taipei Veterans General Hospital from April 1 to July 31, 2022, were enrolled. Comparative analysis of outcomes and safety between patients with or without severe renal impairment (estimated glomerular filtration rate of < 30 mL/min per 1.73 m
2 ) were conducted. Prognostic factors associated with 28-day mortality in patients with severe renal impairment were investigated using logistic regression analysis., Results: A total of 671 hospitalized patients, including 132 patients with severe renal impairment, who received a 5-day course of remdesivir were analyzed. The 28-day mortality was higher in patients with severe renal impairment than in patients without severe renal impairment (15.2% vs. 7.8%). The proportion of patients with acute kidney injury (AKI) and deteriorated liver function after completing remdesivir therapy was similar between the patients with and without severe renal impairment, and the recovery rate of AKI was similar in both groups. The sequential organ failure assessment score was an independent factor associated with 28-day mortality in patients with severe renal impairment., Conclusions: Remdesivir was well-tolerated in hospitalized patients with COVID-19, regardless of renal function. Our findings support the recent recommendation to administer remdesivir in patients with severe renal impairment., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)- Published
- 2024
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20. Magnolol against enterovirus 71 by targeting Nrf2-SLC7A11-GSH pathway.
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Zhao D, Guo X, Lin B, Huang R, Li H, Wang Q, Zeng Y, Shang Y, and Wu Y
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- Animals, Mice, Humans, Glutathione metabolism, Virus Replication drug effects, Reactive Oxygen Species metabolism, Enterovirus Infections drug therapy, Enterovirus Infections virology, Signal Transduction drug effects, Chlorocebus aethiops, Vero Cells, Ferroptosis drug effects, Biphenyl Compounds pharmacology, NF-E2-Related Factor 2 metabolism, Lignans pharmacology, Enterovirus A, Human drug effects, Antiviral Agents pharmacology
- Abstract
Enterovirus 71 (EV71), a prominent pathogen associated with hand, foot, and mouth disease (HFMD), has been reported worldwide. To date, the advancement of effective drugs targeting EV71 remains in the preliminary experimental stage. In this study, magnolol demonstrated a significant dose-dependent inhibition of EV71 replication in vitro. It upregulated the overall expression level of nuclear factor erythroid 2 - related factor 2 (Nrf2) and facilitated its nucleus translocation, resulting in the increased expression of various ferroptosis inhibitory genes. This process led to a reduction in reactive oxygen species (ROS) accumulation induced by viral infection. Additionally, magnolol exhibited a broad-spectrum antiviral effect against enteroviruses. Notably, treatment with magnolol substantially enhanced the survival rate of EV71-infected mice, attenuated viral load in heart, liver, brain, and limb tissues, and mitigated tissue inflammation. Taken together, magnolol emerges as a promising candidate for the development of anti-EV71 drugs., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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21. A high-throughput cell-based screening method for Zika virus protease inhibitor discovery.
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Anindita PD, Otsuka Y, Lattmann S, Ngo KH, Liew CW, Kang C, Harris RS, Scampavia L, Spicer TP, and Luo D
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- Humans, Viral Nonstructural Proteins antagonists & inhibitors, Viral Nonstructural Proteins metabolism, Viral Nonstructural Proteins genetics, Serine Endopeptidases metabolism, Serine Endopeptidases genetics, Animals, Viral Proteases, Nucleoside-Triphosphatase, DEAD-box RNA Helicases, Zika Virus drug effects, High-Throughput Screening Assays methods, Protease Inhibitors pharmacology, Antiviral Agents pharmacology, Drug Discovery methods, Zika Virus Infection virology, Zika Virus Infection drug therapy
- Abstract
Zika virus (ZIKV) continues to pose a significant global public health threat, with recurring regional outbreaks and potential for pandemic spread. Despite often being asymptomatic, ZIKV infections can have severe consequences, including neurological disorders and congenital abnormalities. Unfortunately, there are currently no approved vaccines or antiviral drugs for the prevention or treatment of ZIKV. One promising target for drug development is the ZIKV NS2B-NS3 protease due to its crucial role in the virus life cycle. In this study, we established a cell-based ZIKV protease inhibition assay designed for high-throughput screening (HTS). Our assay relies on the ZIKV protease's ability to cleave a cyclised firefly luciferase fused to a natural cleavage sequence between NS2B and NS3 protease within living cells. We evaluated the performance of our assay in HTS setting using the pharmacologic controls (JNJ-40418677 and MK-591) and by screening a Library of Pharmacologically Active Compounds (LOPAC). The results confirmed the feasibility of our assay for compound library screening to identify potential ZIKV protease inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)
- Published
- 2024
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22. In vitro and in vivo antiviral effects of CLEVir-X against porcine reproductive and respiratory syndrome virus.
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Suh J, Ham S, Kim Y, Kim S, Cho A, Moon H, and Chae C
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- Animals, Swine, Virus Replication drug effects, Lung virology, Lung drug effects, Lung pathology, Viral Load drug effects, Administration, Oral, Porcine respiratory and reproductive syndrome virus drug effects, Porcine respiratory and reproductive syndrome virus genetics, Antiviral Agents pharmacology, Porcine Reproductive and Respiratory Syndrome drug therapy, Porcine Reproductive and Respiratory Syndrome virology
- Abstract
The aim of this study was to investigate the in vitro and in vivo antiviral effects of CLEVir-X, against porcine reproductive and respiratory syndrome virus (PRRSV). CLEVir-X is a nucleoside analogue and a dialdehyde form of xanthosine. CLEVir-X demonstrated antiviral action during the in vitro portion of this experiment with its inosine monophosphate dehydrogenase (IMPDH) inhibition against PRRSV. The anti-PRRSV effect of CLEVir-X was recovered through supplementation with guanosine. This suggests that PRRSV replication may be regulated through IMPDH and its guanosine biosynthetic pathway. CLEVir-X treatment in cultures resulted in mutation frequency increase of up to 7.8-fold within the viral genomes (e.g. ORF6) compared to their parallel, untreated cultures. The incorporation of CLEVir-X into the viral genome causes lethal mutagenesis and subsequent decrease in specific infectivity. During the in vivo antiviral experiment, 21-day-old pigs began oral administration of 5 mL of phosphate buffered saline containing CLEVir-X (with purity of 68 % and dosage of 40 mg/kg body weight). This treatment was provided twice daily at 9:00AM and 5:00PM for 14 days. Pigs were simultaneously intranasally inoculated with PRRSV at the beginning of CLEVir-X treatment (21 days of age). Several beneficial effects from the oral administration of CLEVir-X were observed including reduction of body temperature, alleviation of respiratory clinical signs, decreased PRRSV load in both blood and lung tissues, and mitigation of lung interstitial pneumonia lesions. The results of the present study demonstrated that CLEVir-X has mutagenic and nonmutagenic modes of antiviral action against PRRSV based on both in vitro and in vivo antiviral experiments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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23. Repurposing anti-cancer porphyrin derivative drugs to target SARS-CoV-2 envelope.
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Mendonça DA, Cadima-Couto I, Buga CC, Arnaut ZA, Schaberle FA, Arnaut LG, Castanho MARB, and Cruz-Oliveira C
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- Humans, Caco-2 Cells, COVID-19 Drug Treatment, Antineoplastic Agents pharmacology, Viral Envelope drug effects, Animals, Chlorocebus aethiops, Vero Cells, COVID-19 virology, Porphyrins pharmacology, SARS-CoV-2 drug effects, Drug Repositioning, Antiviral Agents pharmacology
- Abstract
Antiviral medicines to treat COVID-19 are still scarce. Porphyrins and porphyrin derivatives (PDs) usually present broad-spectrum antiviral activity with low risk of resistance development. In fact, some PDs are clinically approved to be used in anti-cancer photodynamic therapy and repurposing clinically approved PDs might be an alternative to treat COVID-19. Here, we characterize the ability of temoporfin, verteporfin, talaporfin and redaporfin to inactivate SARS-CoV-2 infectious particles. PDs light-dependent and -independent effect on SARS-CoV-2 infectivity were evaluated. PDs photoactivation successfully inactivated SARS-CoV-2 with very low concentrations and light dose. However, only temoporfin and verteporfin inactivated SARS-CoV-2 in the dark, being verteporfin the most effective. PDs treatment reduced viral load in infected Caco-2 cells, while not inducing cytotoxicity. Furthermore, light-independent treatment with temoporfin and verteporfin act on early stages of viral infection. Using lipid vehicles as membrane models, we characterized PDs interaction to the viral envelope. Verteporfin presented the lowest IC50 for viral inactivation and the highest partition coefficients (K
p ) towards lipid bilayers. Curiously, although temoporfin and redaporfin presented similar Kp s, redaporfin did not present light-independent antiviral activity, and only temoporfin and verteporfin caused lipid membrane disorder. In fact, redaporfin is located closer to the bilayer surface, while temoporfin and verteporfin are located closer to the centre. Our results suggest that viral envelope affinity, with penetration and destabilization of the lipid bilayer, seems critical to mediate PDs antiviral activity. Altogether, these findings open new avenues for the off-label application of temoporfin and verteporfin in the systemic treatment of COVID-19., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)- Published
- 2024
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24. Antibody drugs targeting SARS-CoV-2: Time for a rethink?
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Liang L, Wang B, Zhang Q, Zhang S, and Zhang S
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- Humans, Antibodies, Viral therapeutic use, Antibodies, Viral immunology, Animals, Mutation, Antibodies, Monoclonal therapeutic use, SARS-CoV-2 drug effects, SARS-CoV-2 immunology, COVID-19 Drug Treatment, Antibodies, Neutralizing therapeutic use, Antibodies, Neutralizing immunology, COVID-19 immunology, COVID-19 virology, Antiviral Agents therapeutic use, Antiviral Agents pharmacology
- Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) heavily burdens human health. Multiple neutralizing antibodies (nAbs) have been issued for emergency use or tested for treating infected patients in the clinic. However, SARS-CoV-2 variants of concern (VOC) carrying mutations reduce the effectiveness of nAbs by preventing neutralization. Uncoding the mutation profile and immune evasion mechanism of SARS-CoV-2 can improve the outcome of Ab-mediated therapies. In this review, we first outline the development status of anti-SARS-CoV-2 Ab drugs and provide an overview of SARS-CoV-2 variants and their prevalence. We next focus on the failure causes of anti-SARS-CoV-2 Ab drugs and rethink the design strategy for developing new Ab drugs against COVID-19. This review provides updated information for the development of therapeutic Ab drugs against SARS-CoV-2 variants., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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25. Interaction and antiviral treatment of coinfection between SARS-CoV-2 and influenza in vitro.
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Liu D, Leung KY, Lam HY, Zhang R, Fan Y, Xie X, Chan KH, and Hung IF
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- Humans, Pyridones pharmacology, Pyridones therapeutic use, Cell Line, Morpholines pharmacology, Morpholines therapeutic use, Triazines pharmacology, Triazines therapeutic use, COVID-19 Drug Treatment, Hydroxylamines pharmacology, Hydroxylamines therapeutic use, Thiazoles pharmacology, Thiazoles therapeutic use, Cytidine analogs & derivatives, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, SARS-CoV-2 drug effects, Influenza, Human drug therapy, Influenza, Human virology, Coinfection drug therapy, Coinfection virology, Virus Replication drug effects, Dibenzothiepins therapeutic use, Influenza A Virus, H1N1 Subtype drug effects, COVID-19 virology, Viral Load drug effects
- Abstract
Background: The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has lasted for three years. Coinfection with seasonal influenza may occur resulting in more severe diseases. The interaction between these two viruses for infection and the effect of antiviral treatment remains unclear., Methods: A SARS-CoV-2 and influenza H1N1 coinfection model on Calu-3 cell line was established, upon which the simultaneous and sequential coinfection was evaluated by comparing the viral load. The efficacy of molnupiravir and baloxavir against individual virus and coinfection were also studied., Results: The replication of SARS-CoV-2 was significantly interfered when the influenza virus was infected simultaneously or in advance (p < 0.05). On the contrary, the replication of the influenza virus was not affected by the SARS-CoV-2. Molnupiravir monotherapy had significant inhibitory effect on SARS-CoV-2 when the concentration reached to 6.25 μM but did not show any significant anti-influenza activity. Baloxavir was effective against influenza within the dosage range and showed significant effect of anti-SARS-CoV-2 at 16 μM. In the treatment of coinfection, molnupiravir had significant effect for SARS-CoV-2 from 6.25 μM to 100 μM and inhibited H1N1 at 100 μM (p < 0.05). The tested dosage range of baloxavir can inhibit H1N1 significantly (p < 0.05), while at the highest concentration of baloxavir did not further inhibit SARS-CoV-2, and the replication of SARS-CoV-2 significantly increased in lower concentrations. Combination treatment can effectively inhibit influenza H1N1 and SARS-CoV-2 replication during coinfection. Compared with molnupiravir or baloxavir monotherapy, combination therapy was more effective in less dosage to inhibit the replication of both viruses., Conclusions: In coinfection, the replication of SARS-CoV-2 would be interfered by influenza H1N1. Compared with molnupiravir or baloxavir monotherapy, treatment with a combination of molnupiravir and baloxavir should be considered for early treatment in patients with SARS-CoV-2 and influenza coinfection., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2024
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26. A mini-review of the anti-SARS-CoV-2 potency of Amaryllidaceae alkaloids.
- Author
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Le NT, Janssen K, Kirchmair J, Pieters L, and Tuenter E
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- Humans, Structure-Activity Relationship, COVID-19 Drug Treatment, Amaryllidaceae chemistry, Amaryllidaceae Alkaloids pharmacology, Amaryllidaceae Alkaloids chemistry, Antiviral Agents pharmacology, Antiviral Agents chemistry, SARS-CoV-2 drug effects
- Abstract
Background: Nature has perennially served as an infinite reservoir of diverse chemicals with numerous applications benefiting humankind. In recent years, due to the emerging COVID-19 pandemic, there has been a surge in studies on repurposing natural products as anti-SARS-CoV-2 agents, including plant-derived substances. Among all types of natural products, alkaloids remain one of the most important groups with various known medicinal values. The current investigation focuses on Amaryllidaceae alkaloids (AAs) since AAs have drawn significant scientific attention as anti-SARS-CoV-2 agents over the past few years., Purpose and Study Design: This study serves as a mini-review, summarizing recent advances in studying the anti-SARS-CoV-2 potency of AAs, covering two aspects: structure-activity relationship and mechanism of action (MOA)., Methods: The study covers the period from 2019 to 2023. The information in this review were retrieved from common databases including Web of Science, ScienceDirect, PubMed and Google scholar. Reported anti-SARS-CoV-2 potency, cytotoxicity and possible biological targets of AAs were summarized and classified into different skeletal subclasses. Then, the structure-activity relationship (SAR) was explored, pinpointing the key pharmacophore-related structural moieties. To study the mechanism of action of anti-SARS-CoV-2 AAs, possible biological targets were discussed., Results: In total, fourteen research articles about anti-SARS-CoV-2 was selected. From the SAR point of view, four skeletal subclasses of AAs (lycorine-, galanthamine-, crinine- and homolycorine-types) appear to be promising for further investigation as anti-SARS-CoV-2 agents despite experimental inconsistencies in determining in vitro half maximal inhibitory effective concentration (EC
50 ). Narciclasine, haemanthamine- and montanine-type skeletons were cytotoxic and devoid of anti-SARS-CoV-2 activity. The lycorine-type scaffold was the most structurally diverse in this study and preliminary structure-activity relationships revealed the crucial role of ring C and substituents on rings A, C and D in its anti-SARS-CoV-2 activity. It also appears that two enantiomeric skeletons (haemanthamine- and crinine-types) displayed opposite activity/toxicity profiles regarding anti-SARS-CoV-2 activity. Pharmacophore-related moieties of the haemanthamine/crinine-type skeletons were the substituents on rings B, C and the dioxymethylene moiety. All galanthamine-type alkaloids in this study were devoid of cytotoxicity and it appears that varying substituents on rings C and D could enhance the anti-SARS-CoV-2 potency. Regarding MOAs, initial experimental results suggested Mpro and RdRp as possible viral targets. Dual functionality between anti-inflammatory activity on host cells and anti-SARS-CoV-2 activity on the SARS-CoV-2 virus of isoquinoline alkaloids, including AAs, were suggested as the possible MOAs to alleviate severe complications in COVID-19 patients. This dual functionality was proposed to be related to the p38 MAPK signaling pathway., Conclusion: Overall, Amaryllidaceae alkaloids appear to be promising for further investigation as anti-SARS-CoV-2 agents. The skeletal subclasses holding the premise for further investigation are lycorine-, crinine-, galanthamine- and homolycorine-types., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier GmbH.)- Published
- 2024
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27. Phenolic compounds of Phellinus spp. with antibacterial and antiviral activities
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Francisco Javier Vazquez-Armenta, Juan Manuel Leyva, Veronica Mata-Haro, Gustavo A. Gonzalez-Aguilar, Manuel R. Cruz-Valenzuela, Martin Esqueda, Aldo Gutierrez, Filomena Nazzaro, Florinda Fratianni, Rigoberto Gaitán-Hernández, and J. Fernando Ayala-Zavala
- Subjects
Phellinus ,Phenols ,Food Microbiology ,Media Technology ,Biotechnology and Industrial Microbiology - Research Paper ,Escherichia coli O157 ,Antiviral Agents ,Listeria monocytogenes ,Microbiology ,Anti-Bacterial Agents - Abstract
Phellinus Quél is one of the largest genera of Hymenochaetaceae; it comprises about 220 species widely distributed on Earth. Most Phellinus species are lignicolous mushrooms that accumulate bioactive compounds. This research studied the phenolic composition of Phellinus spp. and their relationship with antibacterial and antiviral capacity. Phenolics were extracted from Phellinus badius, P. fastuosus, and P. grenadensis; their antiviral and antibacterial activities were evaluated against Listeria monocytogenes, Staphylococcus aureus, Salmonella enterica, and Escherichia coli O157: H7; and the bacteriophages MS2 and Φ- × 174. Gallic acid, chlorogenic acid, caffeic acid, epicatechin, ferulic acid, catechin, 1,3-dicaffeoylquinic acid, p-coumaric acid, and rutin were found in different proportions among Phellinus spp. Total phenolic content ranged from 96 to 209 mg GAE/g, and total flavonoids from 10 to 27 QE/g. The minimum inhibitory concentrations of P. badius, P. grenadensis, and P. fastuosus against E. coli O157: H7 were 13, 20, and 27 mg/mL, against S. enterica were 20, 30, and 15 mg/mL, and against L. monocytogenes were 10, 15, and 25 mg/mL, respectively. The phenolic content was better correlated with the antibacterial effect against E. coli O157: H7 and L. monocytogenes (r = 0.8–0.9), but not against S. enterica (r = 0.05). The antiviral activity of the extracts (0.9 mg/mL) was 29 to 41% against MS2 and 27 to 38% for Φ-X174 virus (r = 0.8–0.9). In silico analysis showed binding energy values of − 7.9 and − 4.8 kcal/mol between the identified phenolic compounds and the M and G proteins of each virus. The antibacterial and antiviral properties of Phellinus species were correlated with the phenolic content.
- Published
- 2022
28. New Pyrazine Conjugates: Synthesis, Computational Studies, and Antiviral Properties against SARS‐CoV‐2
- Author
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Ahmed Kandeil, Mohamed A. Ali, Siva S. Panda, Adel S. Girgis, Ahmed Mostafa, Israa A. Seliem, Yassmin Moatasim, and Mohamed S. Bekheit
- Subjects
1,2,3-Triazole ,Pyrazine ,Computational studies ,Quantitative Structure-Activity Relationship ,Microbial Sensitivity Tests ,Favipiravir ,Antiviral Agents ,Biochemistry ,chemistry.chemical_compound ,Chlorocebus aethiops ,Drug Discovery ,Animals ,General Pharmacology, Toxicology and Pharmaceutics ,Cytotoxicity ,Vero Cells ,Pharmacology ,Coronavirus RNA-Dependent RNA Polymerase ,Molecular Structure ,Full Paper ,SARS-CoV-2 ,Organic Chemistry ,Full Papers ,Benzothiazole ,Amides ,Small molecule ,Combinatorial chemistry ,Molecular Docking Simulation ,chemistry ,Pyrazines ,Click chemistry ,Molecular Medicine ,Conjugate - Abstract
Currently, limited therapeutic options are available for severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2). We have developed a set of pyrazine‐based small molecules. A series of pyrazine conjugates was synthesized by microwave‐assisted click chemistry and benzotriazole chemistry. All the synthesized conjugates were screened against the SAR‐CoV‐2 virus and their cytotoxicity was determined. Computational studies were carried out to validate the biological data. Some of the pyrazine‐triazole conjugates (5 d–g) and (S)‐N‐(1‐(benzo[d]thiazol‐2‐yl)‐2‐phenylethyl)pyrazine‐2‐carboxamide 12 i show significant potency against SARS‐CoV‐2 among the synthesized conjugates. The selectivity index (SI) of potent conjugates indicates significant efficacy compared to the reference drug (Favipiravir)., Antiviral drug development for SARS‐CoV‐2: The design and microwave‐assisted synthesis of pyrazine conjugates are reported. Some of the newly synthesized conjugates show better antiviral activity and selectivity indexes than those of the reference drug. All the lead compounds exhibited low cytotoxicity. Thus, these conjugates could lead to the development of potential drug candidates for SARS‐CoV‐2.
- Published
- 2021
29. OTUD7B deubiquitinates SQSTM1/p62 and promotes IRF3 degradation to regulate antiviral immunity
- Author
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Weihong Xie, Shuo Tian, Jiahui Yang, Sihui Cai, Shouheng Jin, Tao Zhou, Yaoxing Wu, Zhiyun Chen, Yanqin Ji, and Jun Cui
- Subjects
Deubiquitinating Enzymes ,viruses ,Lysine ,Green Fluorescent Proteins ,Pathogen-Associated Molecular Pattern Molecules ,Dextrans ,Cell Biology ,Antiviral Agents ,Nucleotidyltransferases ,Immunity, Innate ,I-kappa B Kinase ,Interferon Type I ,Sequestosome-1 Protein ,Autophagy ,Interferon Regulatory Factor-3 ,RNA, Small Interfering ,Molecular Biology ,Ubiquitins ,Research Paper - Abstract
Deubiquitination plays an important role in the regulation of the crosstalk between macroautophagy/autophagy and innate immune signaling, yet its regulatory mechanisms are not fully understood. Here we identify the deubiquitinase OTUD7B as a negative regulator of antiviral immunity by targeting IRF3 (interferon regulatory factor 3) for selective autophagic degradation. Mechanistically, OTUD7B interacts with IRF3, and activates IRF3-associated cargo receptor SQSTM1/p62 (sequestosome 1) by removing its K63-linked poly-ubiquitin chains at lysine 7 (K7) to enhance SQSTM1 oligomerization. Moreover, viral infection increased the expression of OTUD7B, which forms a negative feedback loop by promoting IRF3 degradation to balance type I interferon (IFN) signaling. Taken together, our study reveals a specific role of OTUD7B in mediating the activation of cargo receptors in a substrate-dependent manner, which could be a potential target against excessive immune responses. Abbreviations: Baf A1: bafilomycin A1; CGAS: cyclic GMP-AMP synthase; DDX58/RIG-I: DExD/H-box helicase 58; DSS: dextran sodium sulfate; DUBs: deubiquitinating enzymes; GFP: green fluorescent protein; IFN: interferon; IKKi: IKBKB/IkappaB kinase inhibitor; IRF3: interferon regulatory factor 3; ISGs: interferon-stimulated genes; MAVS: mitochondrial antiviral signaling protein; MOI: multiplicity of infection; PAMPs: pathogen-associated molecular patterns; SeV: Sendai virus; siRNA: small interfering RNA; SQSTM1/p62: sequestosome 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; Ub: ubiquitin; WT: wild-type; VSV: vesicular stomatitis virus.
- Published
- 2023
30. The discovery of herbal drugs and natural compounds as inhibitors of SARS-CoV-2 infection in vitro
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Ngwe Tun, Mya Myat, Toume, Kazufumi, Luvai, Elizabeth, Nwe, Khine Mya, Mizukami, Shusaku, Hirayama, Kenji, Komatsu, Katsuko, and Morita, Kouichi
- Subjects
Original Paper ,COVID-19 Vaccines ,SARS-CoV-2 ,viruses ,COVID-19 ,Quercus bark ,Antiviral Agents ,Pharmaceutical Preparations ,Humans ,Molecular Medicine ,Baicalin ,Polygala root ,Areca ,Glabridin - Abstract
The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic in 2019 has led to a global health crisis. Mutations of the SARS-CoV-2 genome have impeded the development of effective therapeutics and vaccines against SARS-CoV-2. Natural products are important for discovering therapeutics to treat the 2019 coronavirus disease (COVID-19). In the present study, we investigated the antiviral activity of herbal drug extracts from Polygala Root, Areca, and Quercus Bark and natural compounds derived from herbal drug such as baicalin and glabridin, with IC50 values of 9.5 µg/ml, 1.2 µg/ml, 5.4 µg/ml, 8.8 µM, and 2.5 µM, respectively, against SARS CoV-2 infection in vitro. Certain herbal drug extracts and natural compounds were found to inhibit viral RNA levels and infectious titers of SARS-CoV-2 in a dose-dependent manner. Furthermore, viral protein analyses showed that herbal drug extracts and natural compounds effectively inhibited SARS-CoV-2 in the various entry treatments. Our study revealed that three herbal drugs are good candidates for further in vivo and clinical studies. Supplementary Information The online version contains supplementary material available at 10.1007/s11418-021-01596-w.
- Published
- 2022
31. Evaluating hepatitis C cascade of care surveillance system in Tuscany, Italy, through a population retrospective data-linkage study, 2015–2021.
- Author
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Ceccarelli, Luca, Moretti, Giaele, Mazzilli, Sara, Petri, Davide, Corazza, Ilaria, Rizzo, Caterina, Lucenteforte, Ersilia, Vainieri, Milena, Seghieri, Chiara, and Tavoschi, Lara
- Subjects
HEPATITIS C ,HEPATITIS C virus ,MEDICAL screening ,ANTIVIRAL agents ,HEALTH services accessibility - Abstract
This comprehensive retrospective data-linkage study aimed at evaluating the impact of Direct-Acting Antivirals (DAAs) on Hepatitis C Virus (HCV) testing, treatment trends, and access to care in Tuscany over six years following their introduction. Utilizing administrative healthcare records, our work reveals a substantial increase in HCV tests in 2017, attributed to the decision to provide universal access to treatment. However, despite efforts to eradicate chronic HCV through a government-led plan, the target of treating 6,221 patients annually was not met, and services contracted after 2018, exacerbated by the COVID-19 pandemic. Key findings indicate a higher prevalence of HCV screening among females in the 33–53 age group, influenced by pregnancy-related recommendations, while diagnostic tests and treatment uptake were more common among males. Problematic substance users constituted a significant proportion of those tested and treated, emphasizing their priority in HCV screening. Our paper underscores the need for decentralized HCV models and alternative testing strategies, such as point-of-care assays, especially in populations accessing harm reduction services, communities, and prisons. The study acknowledges limitations in relying solely on administrative records, advocating for improved data access and timely linkages to accurately monitor HCV care cascades and inform regional plans. Despite challenges, the paper demonstrates the value of administrative record linkages in understanding the access to care pathway for hard-to-reach populations. The findings emphasize the importance of the national HCV elimination strategy and the need for enhanced data collection to assess progress accurately, providing insights for future regional and national interventions. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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32. The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Variants and other Viral Infections
- Author
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David Needham
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COVID19 ,Chemistry, Pharmaceutical ,Drug Compounding ,viral infections ,Biological Availability ,Pharmaceutical Science ,Antiviral Agents ,host cell modulation ,universal nasal-throat-spray ,Humans ,Pharmacology (medical) ,Administration, Intranasal ,Aerosols ,Pharmacology ,variants ,pH-dependent-dissolution ,niclosamide-solubility ,Organic Chemistry ,Mucins ,Hydrogen-Ion Concentration ,Viral Load ,COVID-19 Drug Treatment ,Solubility ,Virus Diseases ,Niclosamide ,Pharynx ,Molecular Medicine ,Powders ,Research Paper ,Biotechnology - Abstract
Motivation With the coronavirus pandemic still raging, prophylactic-nasal and early-treatment throat-sprays could help prevent infection and reduce viral load. Niclosamide has the potential to treat a broad-range of viral infections if local bioavailability is optimized as mucin-penetrating solutions that can reach the underlying epithelial cells. Experimental pH-dependence of supernatant concentrations and dissolution rates of niclosamide were measured in buffered solutions by UV/Vis-spectroscopy for niclosamide from different suppliers (AK Sci and Sigma), as precipitated material, and as cosolvates. Data was compared to predictions from Henderson-Hasselbalch and precipitation-pH models. Optical-microscopy was used to observe the morphologies of original, converted and precipitated niclosamide. Results Niclosamide from the two suppliers had different polymorphs resulting in different dissolution behavior. Supernatant concentrations of the “AKSci-polymorph” increased with increasing pH, from 2.53μM at pH 3.66 to 300μM at pH 9.2, reaching 703μM at pH 9.63. However, the “Sigma-polymorph” equilibrated to much lower final supernatant concentrations, reflective of more stable polymorphs at each pH. Similarly, when precipitated from supersaturated solution, or as cosolvates, niclosamide also equilibrated to lower final supernatant concentrations. Polymorph equilibration though was avoided by using a solvent-exchange technique to make the solutions. Conclusions Given niclosamide’s activity as a host cell modulator, optimized niclosamide solutions could represent universal prophylactic nasal and early treatment throat sprays against COVID19, its more contagious variants, and other respiratory viral infections. They are the simplest and potentially most effective formulations from both an efficacy standpoint as well as manufacturing and distribution, (no cold chain). They now just need testing. Supplementary Information The online version contains supplementary material available at 10.1007/s11095-021-03112-x.
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- 2021
33. Long noncoding RNA#45 exerts broad inhibitory effect on influenza a virus replication via its stem ring arms
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Xiufan Liu, Xiaowen Liu, Shunlin Hu, Guoqing Wang, Xiaoquan Wang, Xinxin Zheng, Daxin Peng, Ruyi Gao, Jun Li, Yu Chen, Xinan Jiao, Jiao Hu, Lei Zhang, Min Gu, and Zenglei Hu
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Microbiology (medical) ,replication ,long non-coding rna ,viruses ,Immunology ,Infectious and parasitic diseases ,RC109-216 ,Influenza A Virus, H7N9 Subtype ,Virus Replication ,medicine.disease_cause ,Antiviral Agents ,Microbiology ,Virus ,Cell Line ,Influenza A Virus, H1N1 Subtype ,RNA interference ,Influenza A virus ,medicine ,Humans ,rna-fish ,Polymerase ,antiviral strategy ,Influenza A Virus, H5N1 Subtype ,biology ,RNA ,Virology ,Influenza A virus subtype H5N1 ,influenza a virus ,Infectious Diseases ,Viral replication ,Apoptosis ,biology.protein ,RNA, Long Noncoding ,Parasitology ,Research Article ,Research Paper - Abstract
A growing body of evidence suggests the pivotal role of long non-coding RNA (lncRNA) in influenza virus infection. Based on next-generation sequencing, we previously demonstrated that Lnc45 was distinctively stimulated by H5N1 influenza virus in mice. In this study, we systematically investigated the specific role of Lnc45 during influenza A virus (IAV) infection. Through qRT-PCR, we first demonstrated that Lnc45 is highly up-regulated by different subtypes of IAV strains, including H5N1, H7N9, and H1N1 viruses. Using RNA-FISH and qRT-PCR, we then found that Lnc45 can translocate from nuclear to cytoplasm during H5N1 virus infection. In addition, forced Lnc45 expression dramatically impeded viral replication of H1N1, H5N1, and H7N9 virus, while abolish of Lnc45 expression by RNA interference favored replication of these viruses, highlighting the potential broad antiviral activity of Lnc45 to IAV. Correspondingly, overexpression of Lnc45 inhibited viral polymerase activity and suppressed IAV-induced cell apoptosis. Moreover, Lnc45 significantly restrained nuclear aggregation of viral NP and PA proteins during H5N1 virus infection. Further functional study revealed that the stem ring arms of Lnc45 mainly mediated the antiviral effect. Therefore, we here demonstrated that Lnc45 functions as a broad-spectrum antiviral factor to inhibit influenza virus replication probably through inhibiting polymerase activity and NP and PA nuclear accumulation via its stem ring arms. Our study not only advances our understanding of the complexity of the IAV pathogenesis but also lays the foundation for developing novel anti-IAV therapeutics targeting the host lncRNA.
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- 2021
34. Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo
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Haoran Peng, Cuiling Ding, Liangliang Jiang, Wanda Tang, Yan Liu, Lanjuan Zhao, Zhigang Yi, Hao Ren, Chong Li, Yanhua He, Xu Zheng, Hailin Tang, Zhihui Chen, Zhongtian Qi, and Ping Zhao
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drug resistance ,drug repurposing ,SARS-CoV-2 ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,COVID-19 Drug Treatment ,Cricetinae ,hamster model ,Animals ,Humans ,drug screening ,General Agricultural and Biological Sciences ,D614G variant ,General Environmental Science ,Research Paper ,HeLa Cells - Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis. Clinical candidates with high efficacy, ready availability, and that do not develop resistance are in urgent need. Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture, there are few confirmed antiviral candidates in vivo. In this study, 94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs. Among them, 24 compounds with low cytotoxicity were selected, and of these, 17 compounds also effectively suppressed SARS-CoV-2 infection in HeLa cells transduced with human ACE2. Six compounds disturb multiple processes of the SARS-CoV-2 life cycle. Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2 infection. Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant. Except for cisatracurium, six compounds reduced hamster pulmonary viral load, and IL-6 and TNF-α mRNA when assayed at 4 d postinfection. In particular, sertraline, salinomycin, and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro, suggesting promising application for COVID-19 treatment. Supporting Information The supporting information is available online at 10.1007/s11427-021-2031-7. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.
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- 2021
35. Developmental consequences of children born from mothers with telbivudine treatment during late pregnancy: A prospective study with 3-year follow-up
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Ying Zhang, Wei-Hua Cao, Ming-hui Li, Yao Xie, Xiuzhen Cao, Ying Wang, Zhan Zeng, Fangfang Sun, Wei Yi, and Gang Wan
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Microbiology (medical) ,safety ,Pediatrics ,medicine.medical_specialty ,HBsAg ,Immunology ,Gross motor skill ,Infectious and parasitic diseases ,RC109-216 ,Biology ,medicine.disease_cause ,Antiviral Agents ,Nervous System ,Microbiology ,03 medical and health sciences ,Child Development ,Hepatitis B, Chronic ,Telbivudine ,medicine ,Humans ,Prospective Studies ,Pregnancy Complications, Infectious ,neurological development ,030304 developmental biology ,Hepatitis ,Hepatitis B virus ,0303 health sciences ,Pregnancy ,030306 microbiology ,Infant ,Lamivudine ,medicine.disease ,Infectious Disease Transmission, Vertical ,Treatment Outcome ,Infectious Diseases ,HBeAg ,Motor Skills ,Prenatal Exposure Delayed Effects ,DNA, Viral ,telbivudine ,Female ,Parasitology ,chronic hepatitis b ,pregnancy ,Follow-Up Studies ,Research Article ,Research Paper ,medicine.drug - Abstract
We prospectively investigated the neurological development in infants born from mothers treated with telbivudine (LdT) in the third trimester for prevention of hepatitis B virus (HBV) mother-to-infant transmission. Mothers with high HBV load were assigned to either the LdT group (n = 81, 600 mg of LdT each day from gestational week 28 to delivery) or the Control group (n = 39, untreated). Their infants were followed for 36 months to assess physical and neurological developments with Gesell Developmental Schedule tools. At 12 months after birth, the mean scores in the LdT group for gross motor, fine motor, adaptive, linguistic, and personal social domains were similar to those in the Control group. At 36 months, infants in the LdT group had higher mean scores for gross motor than the Control group (98.42 ± 9.69 vs. 94.54 ± 7.48, P = 0.03). In the LdT group, the rates of normal development were higher for gross motor (96.30% vs. 82.05% P = 0.01) and lower for adaptive (74.07% vs. 92.31% P = 0.02). Multivariate regression analyses showed that exposure to LdT during pregnancy was independently associated with infant’s development in gross motor (OR 6.49, 95% CI 1.37–30.20, P = 0.02) and adaptive (OR 0.18, 95% CI 0.05–0.71, P = 0.01) at 36 months. These results suggest that prenatal LdT exposure might affect neurological development in long-term observation. Abbreviations: LdT: telbivudine; HBV: hepatitis B virus; HBsAg: hepatitis B surface antigen; HBeAg: hepatitis Be antigen; HbsAb: hepatitis B surface antibody; ALT: alanine aminotransferase; NA: nucleoside/nucleotide analog; LAM: lamivudine; MTCT: mother-to-child transmission; GDS: Gesell Developmental Schedule; OR: odds ratio; CI: confidence interval; DQ: developmental quotient; RMB: renminbi; BMI: body mass Index; HBIG: hepatitis B immunoglobulin.
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- 2021
36. Coronavirus transmissible gastroenteritis virus antagonizes the antiviral effect of the microRNA miR-27b via the IRE1 pathway
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Li Feng, Peng Wu, Changlin Wang, Guangzheng Wu, Keliang Wang, Pinghuang Liu, Zhongqing Liu, Wanhai Xu, Honglei Wang, and Mei Xue
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Swine ,inositol-requiring enzyme 1 (IRE1) ,coronavirus ,Biology ,Protein Serine-Threonine Kinases ,medicine.disease_cause ,Antiviral Agents ,General Biochemistry, Genetics and Molecular Biology ,Virus ,Cell Line ,microRNA ,medicine ,Animals ,SOCS6 ,Transcription factor ,General Environmental Science ,Coronavirus ,immune evasion ,Messenger RNA ,Endoplasmic reticulum ,Transmissible gastroenteritis virus ,transmissible gastroenteritis coronavirus (TGEV) ,Virology ,MicroRNAs ,Unfolded protein response ,General Agricultural and Biological Sciences ,Coronavirus Infections ,Research Paper - Abstract
Although the functional parameters of microRNAs (miRNAs) have been explored to some extent, the roles of these molecules in coronavirus infection and the regulatory mechanism of miRNAs in virus infection are still unclear. Transmissible gastroenteritis virus (TGEV) is an enteropathgenic coronavirus and causes high morbidity and mortality in suckling piglets. Here, we demonstrated that microRNA-27b-3p (miR-27b-3p) suppressed TGEV replication by directly targeting porcine suppressor of cytokine signaling 6 (SOCS6), while TGEV infection downregulated miR-27b-3p expression in swine testicular (ST) cells and in piglets. Mechanistically, the decrease of miR-27b-3p expression during TGEV infection was mediated by the activated inositol-requiring enzyme 1 (IRE1) pathway of the endoplasmic reticulum (ER) stress. Further studies showed that when ER stress was induced by TGEV, IRE1 acted as an RNase activated by autophosphorylation and unconventionally spliced mRNA encoding a potent transcription factor, X-box-binding protein 1 (Xbp1s). Xbp1s inhibited the transcription of miR-27 and ultimately reduced the production of miR-27b-3p. Therefore, our findings indicate that TGEV inhibits the expression of an anti-coronavirus microRNA through the IRE1 pathway and suggest a novel way in which coronavirus regulates the host cell response to infection. Supporting Information The supporting information is available online at 10.1007/s11427-021-1967-x. The supporting materials are published as submitted, without typesetting or editing. The responsibility for scientific accuracy and content remains entirely with the authors.
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- 2021
37. Hepatitis C–associated late-onset schizophrenia: a nationwide, population-based cohort study
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Rong-Nan Chien, Ming-Ling Chang, Jur-Shan Cheng, Ming-Shyan Lin, Hsin-Ping Ku, Jing-Hong Hu, and Ming-Yu Chang
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Adult ,Male ,medicine.medical_specialty ,Population ,Taiwan ,Hepacivirus ,Antiviral Agents ,Cohort Studies ,Young Adult ,Internal medicine ,medicine ,Humans ,Pharmacology (medical) ,Cumulative incidence ,Age of Onset ,education ,Biological Psychiatry ,education.field_of_study ,business.industry ,Incidence ,Hepatitis C ,Middle Aged ,medicine.disease ,Confidence interval ,Psychiatry and Mental health ,Schizophrenia ,Cohort ,Female ,Interferons ,business ,Diagnosis of schizophrenia ,Cohort study ,Research Paper - Abstract
Background: Whether infection with the hepatitis C virus (HCV) causes schizophrenia — and whether the associated risk reverses after anti-HCV therapy — is unknown; we aimed to investigate these topics. Methods: We conducted a nationwide, population-based cohort study using the Taiwan National Health Insurance Research Database (TNHIRD). A diagnosis of schizophrenia was based on criteria from the International Classification of Diseases, 9th revision (295.xx). Results: From 2003 to 2012, from a total population of 19 298 735, we enrolled 3 propensity-score-matched cohorts (1:2:2): HCV-treated (8931 HCV-infected patients who had received interferon-based therapy for ≥ 6 months); HCV-untreated (17 862); and HCV-uninfected (17 862) from the TNHIRD. Of the total sample (44 655), 82.81% (36 980) were 40 years of age or older. Of the 3 cohorts, the HCV-untreated group had the highest 9-year cumulative incidence of schizophrenia (0.870%, 95% confidence interval [CI] 0.556%–1.311%; p < 0.001); the HCV-treated (0.251%, 95% CI 0.091%–0.599%) and HCV-uninfected (0.118%, 95% CI 0.062%–0.213%) cohorts showed similar cumulative incidence of schizophrenia (p = 0.33). Multivariate Cox analyses showed that HCV positivity (hazard ratio [HR] 3.469, 95% CI 2.168–5.551) was independently associated with the development of schizophrenia. The HCV-untreated cohort also had the highest cumulative incidence of overall mortality (20.799%, 95% CI 18.739%–22.936%; p < 0.001); the HCV-treated (12.518%, 95% CI 8.707%–17.052%) and HCV uninfected (6.707%, 95% CI 5.533%–8.026%) cohorts showed similar cumulative incidence of mortality (p = 0.12). Limitations: We were unable to determine the precise mechanism of the increased risk of schizophrenia in patients with HCV infection. Conclusion: In a population-based cohort (most aged ≥ 40 years), HCV positivity was a potential risk factor for the development of schizophrenia; the HCV-associated risk of schizophrenia might be reversed by interferon-based antiviral therapy.
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- 2021
38. Acyclovir eco-geno-toxicity in freshwater organisms.
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Nugnes R, Russo C, Di Matteo A, Orlo E, De Rosa E, Lavorgna M, and Isidori M
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- Animals, Reactive Oxygen Species metabolism, Cladocera drug effects, Aquatic Organisms drug effects, Toxicity Tests, Acute, DNA Damage, Reproduction drug effects, Toxicity Tests, Chronic, Mutagens toxicity, Chlorophyta drug effects, Water Pollutants, Chemical toxicity, Fresh Water, Antiviral Agents toxicity, Acyclovir toxicity, Rotifera drug effects
- Abstract
This study explores the eco-geno-toxic impact of Acyclovir (ACV), a widely used antiviral drug, on various freshwater organisms, given its increasing detection in surface waters. The research focused on non-target organisms, including the green alga Raphidocelis subcapitata, the rotifer Brachionus calyciflorus, the cladoceran crustacean Ceriodaphnia dubia, and the benthic ostracod Heterocypris incongruens, exposed to ACV to assess both acute and chronic toxicity. The results indicate that while acute toxicity occurs at environmentally not-relevant concentrations, a significant chronic toxicity for C. dubia (EC
50 = 0.03 µg/L, NOEC = 0.02·10-2 µg/L), highlighted substantial environmental concern. Furthermore, DNA strand breaks and reactive oxygen species detected in C. dubia indicate significant increase at concentrations exceeding 200 µg/L. Regarding environmental risk, the authors identified chronic exposures to acyclovir causing inhibitory effects on reproduction in B. calyciflorus at hundreds of µg/L and hundredths of µg/L for C. dubia as environmentally relevant environmental concentrations. The study concludes by quantifying the toxic and genotoxic risks of ACV showing a chronic risk quotient higher than the critical value of 1and a genotoxic risk quotient reaching this threshold, highlighting the urgent need for a broader risk assessment of ACV for its significant implications for aquatic ecosystems., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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39. Non-peptidic inhibitors targeting SARS-CoV-2 main protease: A review.
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Xiao YQ, Long J, Zhang SS, Zhu YY, and Gu SX
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- Humans, Structure-Activity Relationship, COVID-19 Drug Treatment, Molecular Structure, COVID-19 virology, SARS-CoV-2 drug effects, SARS-CoV-2 enzymology, Antiviral Agents pharmacology, Antiviral Agents chemistry, Coronavirus 3C Proteases antagonists & inhibitors, Coronavirus 3C Proteases metabolism, Protease Inhibitors pharmacology, Protease Inhibitors chemistry
- Abstract
The COVID-19 pandemic continues to pose a threat to global health, and sounds the alarm for research & development of effective anti-coronavirus drugs, which are crucial for the patients and urgently needed for the current epidemic and future crisis. The main protease (M
pro ) stands as an essential enzyme in the maturation process of SARS-CoV-2, playing an irreplaceable role in regulating viral RNA replication and transcription. It has emerged as an ideal target for developing antiviral agents against SARS-CoV-2 due to its high conservation and the absence of homologous proteases in the human body. Among the SARS-CoV-2 Mpro inhibitors, non-peptidic compounds hold promising prospects owing to their excellent antiviral activity and improved metabolic stability. In this review, we offer an overview of research progress concerning non-peptidic SARS-CoV-2 Mpro inhibitors since 2020. The efforts delved into molecular structures, structure-activity relationships (SARs), biological activity, and binding modes of these inhibitors with Mpro . This review aims to provide valuable clues and insights for the development of anti-SARS-CoV-2 agents as well as broad-spectrum coronavirus Mpro inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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40. Synthesis and evaluation of pentacyclic triterpenoids conjugates as novel HBV entry inhibitors targeting NTCP receptor.
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Chen Y, Duan M, Wang X, Xu J, Tian S, Xu X, Duan A, Mahal A, Zhu Y, and Zhu Q
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- Humans, Hep G2 Cells, Structure-Activity Relationship, Molecular Structure, Dose-Response Relationship, Drug, Molecular Docking Simulation, Triterpenes pharmacology, Triterpenes chemistry, Triterpenes chemical synthesis, Hepatitis B Surface Antigens metabolism, Hepatitis B virus drug effects, Hepatitis B virus metabolism, Organic Anion Transporters, Sodium-Dependent antagonists & inhibitors, Organic Anion Transporters, Sodium-Dependent metabolism, Symporters metabolism, Symporters antagonists & inhibitors, Antiviral Agents pharmacology, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Virus Internalization drug effects, Pentacyclic Triterpenes pharmacology, Pentacyclic Triterpenes chemical synthesis, Pentacyclic Triterpenes chemistry
- Abstract
Chronic liver diseases caused by hepatitis B virus (HBV) are the accepted main cause leading to liver cirrhosis, hepatic fibrosis, and hepatic carcinoma. Sodium taurocholate cotransporting polypeptide (NTCP), a specific membrane receptor of hepatocytes for triggering HBV infection, is a promising target against HBV entry. In this study, pentacyclic triterpenoids (PTs) including glycyrrhetinic acid (GA), oleanolic acid (OA), ursolic acid (UA) and betulinic acid (BA) were modified via molecular hybridization with podophyllotoxin respectively, and resulted in thirty-two novel conjugates. The anti-HBV activities of conjugates were evaluated in HepG2.2.15 cells. The results showed that 66% of the conjugates exhibited lower toxicity to the host cells and had significant inhibitory effects on the two HBV antigens, especially HBsAg. Notably, the compounds BA-PPT1, BA-PPT3, BA-PPT4, and UA-PPT3 not only inhibited the secretion of HBsAg but also suppressed HBV DNA replication. A significant difference in the binding of active conjugates to NTCP compared to the HBV PreS1 antigen was observed by SPR assays. The mechanism of action was found to be the competitive binding of these compounds to the NTCP 157-165 epitopes, blocking HBV entry into host cells. Molecular docking results indicated that BA-PPT3 interacted with the amino acid residues of the target protein mainly through π-cation, hydrogen bond and hydrophobic interaction, suggesting its potential as a promising HBV entry inhibitor targeting the NTCP receptor., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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41. TMV-CP based rational design and discovery of α-Amide phosphate derivatives as anti plant viral agents.
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Chen S, Yang Z, Sun W, Tian K, Sun P, and Wu J
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- Structure-Activity Relationship, Molecular Structure, Drug Design, Microbial Sensitivity Tests, Amides chemistry, Amides pharmacology, Amides chemical synthesis, Dose-Response Relationship, Drug, Drug Discovery, Molecular Docking Simulation, Tobacco Mosaic Virus drug effects, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents chemical synthesis, Phosphates chemistry, Phosphates pharmacology, Capsid Proteins antagonists & inhibitors, Capsid Proteins chemistry, Capsid Proteins metabolism
- Abstract
The tobacco mosaic virus coat protein (TMV-CP) is indispensable for the virus's replication, movement and transmission, as well as for the host plant's immune system to recognize it. It constitutes the outermost layer of the virus particle, and serves as an essential component of the virus structure. TMV-CP is essential for initiating and extending viral assembly, playing a crucial role in the self-assembly process of Tobacco Mosaic Virus (TMV). This research employed TMV-CP as a primary target for virtual screening, from which a library of 43,417 compounds was sourced and SH-05 was chosen as the lead compound. Consequently, a series of α-amide phosphate derivatives were designed and synthesized, exhibiting remarkable anti-TMV efficacy. The synthesized compounds were found to be beneficial in treating TMV, with compound 3g displaying a slightly better curative effect than Ningnanmycin (NNM) (EC
50 = 304.54 µg/mL) at an EC50 of 291.9 µg/mL. Additionally, 3g exhibited comparable inactivation activity (EC50 = 63.2 µg/mL) to NNM (EC50 = 67.5 µg/mL) and similar protective activity (EC50 = 228.9 µg/mL) to NNM (EC50 = 219.7 µg/mL). Microscale thermal analysis revealed that the binding of 3g (Kd = 4.5 ± 1.9 µM) to TMV-CP showed the same level with NNM (Kd = 5.5 ± 2.6 µM). Results from transmission electron microscopy indicated that 3g could disrupt the structure of TMV virus particles. The toxicity prediction indicated that 3g was low toxicity. Molecular docking showed that 3g interacted with TMV-CP through hydrogen bond, attractive charge interaction and π-Cation interaction. This research provided a novel α-amide phosphate structure target TMV-CP, which may help the discovery of new anti-TMV agents in the future., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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42. Efficient activation of peracetic acid by cobalt modified nitrogen-doped carbon nanotubes for drugs degradation: Performance and mechanism insight.
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Yao M, Zhang S, Xie M, Zhao L, and Zhao RS
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- Catalysis, Water Pollutants, Chemical chemistry, Acyclovir chemistry, Adsorption, Nanotubes, Carbon chemistry, Nitrogen chemistry, Cobalt chemistry, Peracetic Acid chemistry, Antiviral Agents chemistry
- Abstract
Peracetic acid (PAA) has garnered significant attention as a novel disinfectant owing to its remarkable oxidative capacity and minimal potential to generate byproducts. In this study, we prepared a novel catalyst, denoted as cobalt modified nitrogen-doped carbon nanotubes (Co@N-CNTs), and evaluated it for PAA activation. Modification with cobalt nanoparticles (∼4.8 nm) changed the morphology and structure of the carbon nanotubes, and greatly improved their ability to activate PAA. Co@N-CNTs/PAA catalytic system shows outstanding catalytic degradation ability of antiviral drugs. Under neutral conditions, with a dosage of 0.05 g/L Co@N-CNT-9.8 and 0.25 mM PAA, the removal efficiency of acyclovir (ACV) reached 98.3% within a mere 10 min. The primary reactive species responsible for effective pollutant degradation were identified as acetylperoxyl radicals (CH
3 C(O)OO•) and acetyloxyl radicals (CH3 C(O)O•). In addition, density functional theory (DFT) proved that Co nanoparticles, as the main catalytic sites, were more likely to adsorb PAA and transfer more electrons than N-doped graphene. This study explored the feasibility of PAA degradation of antiviral drugs in sewage, and provided new insights for the application of heterogeneous catalytic PAA in environmental remediation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)- Published
- 2024
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43. A path from synthesis to emergency use authorization of molnupiravir as a COVID-19 therapy.
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Sakander N, Ahmed A, Bhardwaj M, Kumari D, Nandi U, and Mukherjee D
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- Humans, Uridine pharmacology, Uridine analogs & derivatives, Uridine chemical synthesis, Uridine chemistry, Uridine therapeutic use, Pandemics, Betacoronavirus drug effects, Coronavirus Infections drug therapy, Pneumonia, Viral drug therapy, Antiviral Agents pharmacology, Antiviral Agents chemistry, Antiviral Agents therapeutic use, Antiviral Agents chemical synthesis, Hydroxylamines therapeutic use, Hydroxylamines chemistry, Hydroxylamines pharmacology, COVID-19 virology, SARS-CoV-2 drug effects, Cytidine analogs & derivatives, Cytidine therapeutic use, Cytidine pharmacology, Cytidine chemistry, Cytidine chemical synthesis, COVID-19 Drug Treatment
- Abstract
Coronaviruses are a group of enveloped viruses with non-segmented, single-stranded, and positive-sense RNA genomes. It belongs to the 'Coronaviridae family', responsible for various diseases, including the common cold, SARS, and MERS. The COVID-19 pandemic, which began in March 2020, has affected 209 countries, infected over a million people, and claimed over 50,000 lives. Significant efforts have been made by repurposing several approved drugs including antiviral, to combat the COVID-19 pandemic. Molnupiravir is found to be the first orally acting efficacious drug to treat COVID-19 cases. It was approved for medical use in the UK in November 2021 and other countries, including USFDA, which granted approval an emergency use authorization (EUA) for treating adults with mild to moderate COVID-19 patients. Considering the importance of molnupiravir, the present review deals with its various synthetic strategies, pharmacokinetics, bio-efficacy, toxicity, and safety profiles. The comprehensive information along with critical analysis will be very handy for a wide range of audience including medicinal chemists in the arena of antiviral drug discovery especially anti-viral drugs against any variant of COVID-19., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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44. Preclinical development of humanized monoclonal antibodies against CD169 as a broad antiviral therapeutic strategy.
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Resa-Infante P, Erkizia I, Muñiz-Trabudua X, Linty F, Bentlage AEH, Perez-Zsolt D, Muñoz-Basagoiti J, Raïch-Regué D, Izquierdo-Useros N, Rispens T, Vidarsson G, and Martinez-Picado J
- Subjects
- Humans, Animals, COVID-19 Drug Treatment, Virus Internalization drug effects, SARS-CoV-2 immunology, SARS-CoV-2 drug effects, Sialic Acid Binding Ig-like Lectin 1 immunology, Antibodies, Monoclonal, Humanized pharmacology, Antibodies, Monoclonal, Humanized therapeutic use, Antibodies, Monoclonal, Humanized immunology, Antiviral Agents pharmacology, Antiviral Agents therapeutic use
- Abstract
New therapies to treat or prevent viral infections are essential, as recently observed during the COVID-19 pandemic. Here, we propose a therapeutic strategy based on monoclonal antibodies that block the specific interaction between the host receptor Siglec-1/CD169 and gangliosides embedded in the viral envelope. Antibodies are an excellent option for treating infectious diseases based on their high specificity, strong targeting affinity, and relatively low toxicity. Through a process of humanization, we optimized monoclonal antibodies to eliminate sequence liabilities and performed biophysical characterization. We demonstrated that they maintain their ability to block viral entry into myeloid cells. These molecular improvements during the discovery stage are key if we are to maximize efforts to develop new therapeutic strategies. Humanized monoclonal antibodies targeting CD169 provide new opportunities in the treatment of infections caused by ganglioside-containing enveloped viruses, which pose a constant threat to human health. In contrast with current neutralizing antibodies that bind antigens on the infectious particle, our antibodies can prevent several types of enveloped viruses interacting with host cells because they target the host CD169 protein, thus becoming a potential pan-antiviral therapy., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J. Martinez-Picado reports financial support from the Spanish Ministry of Science, Innovation and Universities (grants PID2022–139271OB-I00 and CB21/13/00063) and in part by Grifols. His laboratory has been funded by the NIH/NIAID (1 UM1 AI164561–01 and 1P01AI178376–01), EU HORIZON-HLTH-2021-DISEASE-04–07 (grants 101057100 and 101095606, European Union), Fundació La Marató de TV3 (grant 202130–30–31–32, Spain), and Generalitat de Valencia (grant PROMETEO/2021/036, Spain). He has also received institutional grants and educational/consultancy fees from AbiVax, AstraZeneca, Gilead Sciences, Grifols, Janssen, Merck Sharp & Dohme, and ViiV Healthcare, all outside the submitted work. P. Resa-Infante reports financial support from the Government of Catalonia Agency for Administration of University and Research Grants. N. Izquierdo-Useros reports financial support from the Spain Ministry of Science and Innovation and Universities (grant PID2020–117145RB-I00 and 10.13039/501100011033, Spain) and EU HORIZON-HLTH-2021CORONA-01 (grant 101046118, European Union). She also has received institutional funding from Pharma Mar, Grifols, HIPRA, and Amassence, all outside the submitted work. A patent application based on this work has been filed with the European Patent Office (Application form no.: EP23382072) that include P. Resa-Infante, I. Erkizia, N. Izquierdo-Useros and J. Martinez-Picado as inventors.The remaining authors declare that they have no known competing financial interests or personal relationships that could affect the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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45. Discovery of a potent inhibitor, D-132, targeting AsfvPolX, via protein-DNA complex-guided pharmacophore screening and in vitro molecular characterizations.
- Author
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Wu YC, Lai HX, Li JM, Fung KM, and Tseng TS
- Subjects
- Animals, African Swine Fever virology, Swine, Drug Discovery, Virus Replication drug effects, Drug Evaluation, Preclinical, Protein Binding, Molecular Docking Simulation, DNA, Viral genetics, Pharmacophore, African Swine Fever Virus drug effects, African Swine Fever Virus genetics, African Swine Fever Virus chemistry, Antiviral Agents pharmacology, Antiviral Agents chemistry, DNA-Directed DNA Polymerase
- Abstract
The heightened transmissibility and capacity of African swine fever virus (ASFV) induce fatal diseases in domestic pigs and wild boars, posing significant economic repercussions and global threats. Despite extensive research efforts, the development of potent vaccines or treatments for ASFV remains a persistent challenge. Recently, inhibiting the AsfvPolX, a key DNA repair enzyme, emerges as a feasible strategy to disrupt viral replication and control ASFV infections. In this study, a comprehensive approach involving pharmacophore-based inhibitor screening, coupled with biochemical and biophysical analyses, were implemented to identify, characterize, and validate potential inhibitors targeting AsfvPolX. The constructed pharmacophore model, Phar-PolX-S, demonstrated efficacy in identifying a potent inhibitor, D-132 (IC
50 = 2.8 ± 0.2 µM), disrupting the formation of the AsfvPolX-DNA complex. Notably, D-132 exhibited strong binding to AsfvPolX (KD = 6.9 ± 2.2 µM) through a slow-on-fast-off binding mechanism. Employing molecular modeling, it was elucidated that D-132 predominantly binds in-between the palm and finger domains of AsfvPolX, with crucial residues (R42, N48, Q98, E100, F102, and F116) identified as hotspots for structure-based inhibitor optimization. Distinctively characterized by a 1,2,5,6-tetrathiocane with modifications at the 3 and 8 positions involving ethanesulfonates, D-132 holds considerable promise as a lead compound for the development of innovative agents to combat ASFV infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2024
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46. Design, synthesis, docking, and antiviral evaluation of some novel pyrimidinone-based α-aminophosphonates as potent H1N1 and HCoV-229E inhibitors.
- Author
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Hekal HA, Hammad OM, El-Brollosy NR, Salem MM, and Allayeh AK
- Subjects
- Humans, Structure-Activity Relationship, Molecular Structure, Dose-Response Relationship, Drug, Microbial Sensitivity Tests, Neuraminidase antagonists & inhibitors, Neuraminidase metabolism, RNA-Dependent RNA Polymerase antagonists & inhibitors, RNA-Dependent RNA Polymerase metabolism, Antiviral Agents pharmacology, Antiviral Agents chemical synthesis, Antiviral Agents chemistry, Influenza A Virus, H1N1 Subtype drug effects, Molecular Docking Simulation, Drug Design, Pyrimidinones pharmacology, Pyrimidinones chemical synthesis, Pyrimidinones chemistry, Organophosphonates pharmacology, Organophosphonates chemistry, Organophosphonates chemical synthesis, Coronavirus 229E, Human drug effects
- Abstract
Dialkyl/aryl aminophosphonates, 3a-g and 4a-e were synthesized using the LiClO
4 catalyzed Kabachnic Fields-type reaction straightforwardly and efficiently. The synthesized phosphonates structures were characterized using elemental analyses, FT-IR,1 H NMR,13 C NMR, and MS spectroscopy. The new compounds were subjected to in-silico molecular docking simulations to evaluate their potential inhibition against Influenza A Neuraminidase and RNA-dependent RNA polymerase of human coronavirus 229E. Subsequently, the compounds were further tested in vitro using a cytopathic inhibition assay to assess their antiviral activity against both human Influenza (H1N1) and human coronavirus (HCoV-229E). Diphenyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (furan-2-yl) methyl) phosphonate (3f) and diethyl ((2-(5-cyano-6-oxo-4-phenyl-1,6-dihydropyrimidin-2-yl) hydrazinyl) (1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) methyl) phosphonate (4e) were demonstrated direct inhibition activity against Influenza A Neuraminidase and RNA-dependent RNA polymerase. This was supported by their highly favorable binding energies in-silico, with top-ranked values of -12.5 kcal/mol and -14.2 kcal/mol for compound (3f), and -13.5 kcal/mol and -9.89 kcal/mol for compound (4e). Moreover, they also displayed notable antiviral efficacy in vitro against both viruses. These compounds demonstrated significant antiviral activity, as evidenced by selectivity indices (SI) of 101.7 and 51.8, respectively against H1N1, and 24.5 and 5.1 against HCoV-229E, respectively., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hend A. Hekal reports administrative support, article publishing charges, equipment, drugs, or supplies, statistical analysis, travel, and writing assistance were provided by Tanta University Faculty of Science. Hend A. Hekal reports a relationship with Tanta University Faculty of Science that includes: employment and non-financial support. Hend A. Hekal has patent pending to none. none If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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47. Natural Product-Derived Phytochemicals for Influenza A Virus (H1N1) Prevention and Treatment.
- Author
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Li R, Han Q, Li X, Liu X, and Jiao W
- Subjects
- Humans, Animals, Flavonoids chemistry, Flavonoids pharmacology, Flavonoids therapeutic use, Influenza A Virus, H1N1 Subtype drug effects, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Antiviral Agents chemistry, Phytochemicals therapeutic use, Phytochemicals pharmacology, Phytochemicals chemistry, Biological Products pharmacology, Biological Products chemistry, Biological Products therapeutic use, Influenza, Human drug therapy, Influenza, Human prevention & control
- Abstract
Influenza A (H1N1) viruses are prone to antigenic mutations and are more variable than other influenza viruses. Therefore, they have caused continuous harm to human public health since the pandemic in 2009 and in recent times. Influenza A (H1N1) can be prevented and treated in various ways, such as direct inhibition of the virus and regulation of human immunity. Among antiviral drugs, the use of natural products in treating influenza has a long history, and natural medicine has been widely considered the focus of development programs for new, safe anti-influenza drugs. In this paper, we focus on influenza A (H1N1) and summarize the natural product-derived phytochemicals for influenza A virus (H1N1) prevention and treatment, including marine natural products, flavonoids, alkaloids, terpenoids and their derivatives, phenols and their derivatives, polysaccharides, and derivatives of natural products for prevention and treatment of influenza A (H1N1) virus. We further discuss the toxicity and antiviral mechanism against influenza A (H1N1) as well as the druggability of natural products. We hope that this review will facilitate the study of the role of natural products against influenza A (H1N1) activity and provide a promising alternative for further anti-influenza A drug development.
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- 2024
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48. Highly sensitive detection of multiple antiviral drugs using graphitized hydroxylated multi-walled carbon nanotubes/ionic liquids-based electrochemical sensors.
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Zhang Z, Zheng H, Liu Y, Ma S, Feng Q, Qu J, and Zhu X
- Subjects
- Limit of Detection, Electrodes, Graphite chemistry, Antiviral Agents analysis, Antiviral Agents chemistry, Nanotubes, Carbon chemistry, Ionic Liquids chemistry, Electrochemical Techniques instrumentation, Electrochemical Techniques methods
- Abstract
Global outbreaks and the spread of viral diseases in the recent years have led to a rapid increase in the usage of antiviral drugs (ATVs), the residues and metabolites of which are discharged into the natural environment, posing a serious threat to human health. There is an urgent need to develop sensitive and rapid detection tools for multiple ATVs. In this study, we developed a highly sensitive electrochemical sensor comprising a glassy carbon electrode (GCE) modified with graphitized hydroxylated multi-walled carbon nanotubes (G-MWCNT-OH) and 1-butyl-3-methylimidazolium hexafluorophosphate (BMIMPF
6 , IL) for the detection of six ATVs including famciclovir (FCV), remdesivir (REM), favipiravir (FAV), hydroxychloroquine sulfate (HCQ), cepharanthine (CEP) and molnupiravir (MOL). The morphology and structure of the G-MWCNT-OH/IL nanocomposites were characterized comprehensively, and the electroactive surface area and electron conductivity of G-MWCNT-OH/IL/GCE were determined using cyclic voltammetry and electrochemical impedance spectroscopy. The thermodynamic stability and non-covalent interactions between the G-MWCNT-OH and IL were evaluated through quantum chemical simulation calculations, and the mechanism of ATV detection using the G-MWCNT-OH/IL/GCE was thoroughly examined. The detection conditions were optimized to improve the sensitivity and stability of electrochemical sensors. Under the optimal experimental conditions, the G-MWCNT-OH/IL/GCE exhibited excellent electrocatalytic performance and detected the ATVs over a wide concentration range (0.01-120 μM). The limit of detections (LODs) were 42.3 nM, 55.4 nM, 21.9 nM, 15.6 nM, 10.6 nM, and 3.2 nM for FCV, REM, FAV, HCQ, CEP, and MOL, respectively. G-MWCNT-OH/IL/GCE was also highly stable and selective to the ATVs in the presence of multiple interfering analytes. This sensor exhibited great potential for enabling the quantitative detection of multiple ATVs in actual water environment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)- Published
- 2024
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49. Indirubin-3'-monoxime exhibits potent antiviral and anti-inflammatory effects against human adenoviruses in vitro and in vivo.
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Wang J, Yang C, Liang Z, Sun J, Zhang M, Qiu S, Du X, He X, Pang X, Ma X, Xie M, Han X, Fan R, Zhou E, Yu H, She D, Song H, and Wang J
- Subjects
- Animals, Humans, Mice, Mice, Transgenic, Adenovirus Infections, Human drug therapy, Adenovirus Infections, Human virology, A549 Cells, Cytokines metabolism, Phosphorylation drug effects, Indoles pharmacology, Oximes pharmacology, Antiviral Agents pharmacology, Adenoviruses, Human drug effects, Virus Replication drug effects, Anti-Inflammatory Agents pharmacology
- Abstract
Human adenovirus (HAdV) infection is a major cause of respiratory disease, yet no antiviral drugs have been approved for its treatment. Herein, we evaluated the antiviral and anti-inflammatory effects of cyclin-dependent protein kinase (CDK) inhibitor indirubin-3'-monoxime (IM) against HAdV infection in cells and a transgenic mouse model. After evaluating its cytotoxicity, cytopathic effect reduction, antiviral replication kinetics, and viral yield reduction assays were performed to assess the anti-HAdV activity of IM. Quantitative real-time polymerase chain reaction (qPCR), quantitative reverse transcription PCR (qRT-PCR), and western blotting were used to assess the effects of IM on HAdV DNA replication, transcription, and protein expression, respectively. IM significantly inhibited HAdV DNA replication as well as E1A and Hexon transcription, in addition to significantly suppressing the phosphorylation of the RNA polymerase II C-terminal domain (CTD). IM mitigated body weight loss, reduced viral burden, and lung injury, decreasing cytokine and chemokine secretion to a greater extent than cidofovir. Altogether, IM inhibits HAdV replication by downregulating CTD phosphorylation to suppress viral infection and corresponding innate immune reactions as a promising therapeutic agent., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper, (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)
- Published
- 2024
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50. Novel antivirals for severe enterovirus infection in immunocompromised hosts; A case series.
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Meinhardt A, Reilly L, Kaliakatsos M, Abdel-Aziz K, Alsharidah S, Bodi I, Booth C, Chetty K, Evans J, Ferreras-Antolín L, Froude S, Galtrey CM, Guruprasad S, Hadden RD, Hassell J, Hyöty H, Kreins AY, Laiho JE, Lowe DM, Lunn MP, Mankad K, Struik S, Whittaker E, Worth A, Yong P, Zhang L, Breuer J, and Kadambari S
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Female, Humans, Male, Middle Aged, Enterovirus, Antiviral Agents therapeutic use, Enterovirus Infections drug therapy, Immunocompromised Host
- Abstract
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
- Published
- 2024
- Full Text
- View/download PDF
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