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Graphical abstract, The clinical manifestation of the recent pandemic COVID-19, caused by the novel SARS-CoV-2 virus, varies from mild to severe respiratory illness. Although environmental, demographic and co-morbidity factors have an impact on the severity of the disease, contribution of the mutations in each of the viral genes towards the degree of severity needs a deeper understanding for designing a better therapeutic approach against COVID-19. Open Reading Frame-3a (ORF3a) protein has been found to be mutated at several positions. In this work, we have studied the effect of one of the most frequently occurring mutants, D155Y of ORF3a protein, found in Indian COVID-19 patients. Using computational simulations we demonstrated that the substitution at 155th changed the amino acids involved in salt bridge formation, hydrogen-bond occupancy, interactome clusters, and the stability of the protein compared with the other substitutions found in Indian patients. Protein–protein docking using HADDOCK analysis revealed that substitution D155Y weakened the binding affinity of ORF3a with caveolin-1 compared with the other substitutions, suggesting its importance in the overall stability of ORF3a-caveolin-1 complex, which may modulate the virulence property of SARS-CoV-2.

Summary: Objectives: Patients with coronavirus disease 2019 (COVID-19) can present anorexia and weight loss due to their symptoms and eating disorder which can lead to immune system weakness and increase the duration of recovery time. We aim to assess the severity and duration of anorexia and weight loss within the infection and recovery period in these patients. Method: We retrospectively identified 233 COVID-19 patients (older than 18 years) were admitted to the Rasoul-e Akram Hospital, from August to December 2020. Their medical records were reviewed by researchers. Then, patients who had inclusion criteria were asked about duration and severity of anorexia, and also weight alternation during the infection and after the recovery period. Result: Analyzed data were collected from 233 COVID-19 patients showed the mean duration of anorexia was 7.08 ± 10.41 days with a significant loss of appetite (- 75.55 ± 88.09, P-value < 0.001) at the period of anorexia compare to appetite improvement. Also, results demonstrated patients, especially males and severe illness subjects, significantly lost weight (P-value

Coronaviruses are a large family of viruses that cause illnesses ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS), and the 2019 novel coronavirus infection (COVID-19). Currently, there is no analyzed data to examine the outbreak of COVID-19 by continent and no determination of prevalence trends; this article reviews COVID-19 epidemiology and immunology. Original research, reviews, governmental databases, and treatment guidelines are analyzed to present the epidemiology and immunology of COVID-19. Reports from patients who were COVID-19 infected showed typical symptoms of neutrophilia, lymphopenia, and increased systemic inflammatory proteins of IL-6 and C reactive protein (CRP). These observations agree with the results of severe conditions of MERS or lethal cases of SARS, in which there is an increased presence of neutrophils and macrophages in the airways. Additionally, analyzed data showed that Europe (49.37%), the Americas (27.4%), and Eastern Mediterranean (10.07%) had the most cumulative total per 100,000 population confirmed cases, and Africa (6.9%), Western Pacific (3.46%), and South-East Asia (2.72%) had the lowest cumulative total per 100,000 population confirmed cases. In general, the trend lines showed that the number of confirmed cases (cumulative total) and deaths (cumulative total) would decrease eventually.

Background: Over the last two decades, humanity has observed the extraordinary anomaly caused by novel, weird coronavirus strains, such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). As the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus has made its entry into the world, it has dramatically affected life in every domain by continuously producing new variants. The vaccine development is an ongoing process, although some vaccines got marketed. The big challenge is now whether the vaccine candidates can provide long-lasting protection or prevention against mutant variants. Methods: The information was gathered from various journals, electronic searches via Internet-based information such as PubMed, Google Scholar, Science Direct, online electronic journals, WHO landscape, world meters, WHO website, and News. Results: This review will present and discuss some coronavirus disease 19 (COVID-19) related aspects including: the pathophysiology, epidemiology, mutant variants vaccine candidates, vaccine efficacy, and management strategies. Due to the high death rate, continuous spread, an inadequate workforce, lack of required therapeutics, and incomplete understanding of the viral strain, it becomes crucial to build the knowledge of its biological characteristics and make available the rapid diagnostic and vital therapeutic machinery for the combat and management of an infection. Conclusion: The data summarizes current research on the COVID 19 infection and therapeutic interventions, which will direct future decision-making on the effort-worthy phases of the COVID 19 and the development of critical therapeutics. The only possible solution is the vaccine development targeting against all variant strains to halt its progress; the identified theoretical and practical knowledge can eliminate the gaps to improve a better understanding of the novel coronavirus structure and its design of a vaccine. In addition, to that the long-lasting protection is another challenging objective that need to be looked into.

COVID-19, caused by SARS-CoV-2, is a highly infectious disease, and clinical laboratory detection has played important roles in its diagnosis and in evaluating progression of the disease. Nucleic acid amplification testing or gene sequencing can serve as pathogenic evidence of COVID-19 diagnosing for clinically suspected cases, and dynamic monitoring of specific antibodies (IgM, IgA, and IgG) is an effective complement for false-negative detection of SARS-CoV-2 nucleic acid. Antigen tests to identify SARS-CoV-2 are recommended in the first week of infection, which is associated with high viral loads. Additionally, many clinical laboratory indicators are abnormal as the disease evolves. For example, from moderate to severe and critical cases, leukocytes, neutrophils, and the neutrophil-lymphocyte ratio increase; conversely, lymphocytes decrease progressively but are over activated. LDH, AST, ALT, CK, high-sensitivity troponin I, and urea also increase progressively, and increased D-dimer is an indicator of severe disease and an independent risk factor for death. Severe infection leads to aggravation of inflammation. Inflammatory biomarkers and cytokines, such as CRP, SAA, ferritin, IL-6, and TNF-α, increase gradually. High-risk COVID-19 patients with severe disease, such as the elderly and those with underlying diseases (cardiovascular disease, diabetes, chronic respiratory disease, hypertension, obesity, and cancer), should be monitored dynamically, which will be helpful as an early warning of serious diseases.

OBJECTIVE: To explore whether convalescent plasma therapy is beneficial to patients with severe acute respiratory infections and gave hints to the management of COVID-19. METHODS: A comprehensive literature search of PubMed, Web of Science, Embase, and Cochrane library was conducted for all eligible studies range from inception to February 29, 2020. Studies with control group were included. Treatment group received convalescent plasma therapy, and control group may receive any therapy other than convalescent plasma therapy. Odds ratios (ORs), mean differences (MDs) and 95% confidence intervals (CIs) were pooled for categorical and continuous outcomes. RESULTS: A total of 1997 patients from 13 studies were included, and seven studies were prospectively designed. Pooled analysis indicated convalescent plasma treatment significantly reduced the mortality by 51% (OR=0.49, 95% CI: 0.36 to 0.67). Subgroup analyses by publication time, study design, and influenza A revealed similar results. Sensitivity analyses suggested that the results were stable. In addition, convalescent plasma therapy reduced mechanical ventilation requirement (OR: 0.35, 95% CI: 0.21 to 0.59), while it was not associated with less use of extracorporeal membrane oxygenation (OR: 2.0, 95% CI: 0.83 to 4.83) and shorter length of hospital stay (MD: -2.20, 95% CI: -4.98 to 0.57days). Pooled estimates showed there was no difference in serious adverse effects between the convalescent plasma treatment and control groups (OR: 0.75, 95% CI: 0.50 to 1.13). CONCLUSION: Convalescent plasma therapy significantly reduced the mortality and mechanical ventilation requirements of patients with virus-induced severe acute respiratory infections, without serious adverse effects. More studies are needed to explore whether this treatment can be extrapolated into COVID-19.

HLA alleles are associated with the body's response to infection and the regulation of the immune system. HLA alleles have been reported to be involved in response to viral infections such as SARS-CoV2. Our study reviews the HLA alleles associated with protection or susceptibility to SARS-CoV2 and the prevalence of these HLA alleles in South America. Previous studies on HLA and SARS-CoV2 infection reported that HLA-A*02:02, HLA-B*15:03, and HLA-C*12:03 are protective; while HLA-A*25:01, HLA-B*46:01, and HLA-C*01:02 increase susceptibility. We identified that these alleles are not frequent in South America, confirmed that the spike protein is the most immunogenic protein of SARS-CoV2, and detected new immunogenic epitopes that bound to protective HLA alleles and to HLA alleles common in South America (binding score > 0.90). These could be used as vaccine targets.

Summary Background In Covid-19 pneumonia, high mortality rates reported in intubated patients have raised non-invasive methods of respiratory support. Objective We aimed to evaluate the impact of HFNC application on intubation requirement, intensive care length of stay, and short-term mortality in patients with COVID-19 pneumonia. Material-method Patients receiving oxygen by reservoir mask or HFNC therapy in our intensive care units due to COVID-19 pneumonia were included in the study. Group H consisted of patients who received HFNC, and Group K consisted of patients who received conventional oxygen therapy (COT). The number of patients intubated, duration of intensive care stay and short-term mortality were recorded. Results 43 patients were included. The short-term mortality and the number of patients with intubation need was lower in Group H. There was no significant difference between the Groups in the length of intensive care stay. Conclusion Administration of HFNC in respiratory failure secondary to COVID-19 pneumonia decreases the need for intubation and mortality.

SARS-CoV-2 is a recently identified coronavirus accountable for the current pandemic disease known as COVID-19. Different patterns of disease progression infer a diverse host immune response, with interferon (IFN) being pivotal. IFN-I and III are produced and released by virus-infected cells during the interplay with SARS-CoV-2, thus establishing an antiviral state in target cells. However, the efficacy of IFN and its role in the possible outcomes of the disease are not yet defined, as it is influenced both by factors inherent to the virus and to the host. The virus exhibits multiple strategies to counteract the innate immune response, including those shared by SARS-CoV and MERS-CoV and other novel ones. Inborn errors in the host may affect IFN-related effector proteins or decrease its levels in plasma upon neutralization by preexistent autoantibodies. This battle between the IFN response triggered upon SARS-CoV-2 infection, its magnitude and timing, and the efficacy of its antiviral tools in dispute against the viral evasion strategies together with the genetic factors of the host, generate a scenario whose fate contributes to defining the severity of COVID-19.

Background Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is associated with a high fatality rate (34%), which is higher in the presence of co-morbidities. The aim of the current study was to assess the clinical course and the outcome in hematological or oncological malignancy cases, diagnosed with MERS-CoV. Methods This is a case series of hematological /oncological cases, diagnosed with MERS-CoV, in a tertiary care setting in 2015. The cases were identified based on the World Health Organization (WHO) MERS-CoV case definition. The demographic, clinical, and outcome data were retrieved from the patients’ medical charts and electronic health records. Results In total, nine hematological or oncological cases were identified, diagnosed with MERS-CoV. The baseline malignant condition was hematological malignancy in seven patients, as well as colon cancer and osteosarcoma in one patient each. Six (67%) patients were male. The median age was 65 years (range 16–80 years). Co-morbidities included chronic kidney disease (n = 3.33%), diabetes mellitus (n = 3.33%), and hypertension (n = 2.22%). The presenting symptoms were shortness of breath (n = 6.66%), fever (n = 5.55%), cough (n = 2.22%), and diarrhea (n = 2.22%). Chest x-rays indicated bilateral infiltrates in 6 patients (66%). The PCR (polymerase chain reaction) test was repeated in six patients to confirm the diagnosis. The mortality rate was 100%, and the median time to death was 26 days (range 15–77 days). Conclusion MERS-CoV infection in this small cohort of hematology or oncology patients has a 100% mortality rate, regardless of the status of the underlying disease. The confirmation of the diagnosis may require repeated testing. Additional studies are required to verify the findings and to elucidate the disease pathogenesis in cancer patients.

Background: The aim of this research is to assess the predictive accuracy of the Infectious Diseases Seeker (IDS) – an innovative tool for prompt identification of the causative agent of infectious diseases during outbreaks – when field epidemiological data collected from a novel outbreak of unknown origin are analysed by the tool. For this reason, it has been taken into account the novel coronavirus disease (COVID-19) outbreak, which began in China at the end of December 2019, has rapidly spread around the globe, and it has led to a public health emergency of international concern (PHEIC), declared to the 30th of January 2020 by the World Health Organization (WHO). Methods: The IDS takes advantage of an off-line database, built before the COVID-19 pandemic, which represents a pivotal characteristic for working without an internet connection. The software has been tested using the epidemiological data available in different and progressive stages of the COVID-19 outbreak. As a comparison, the results of the tests performed using the epidemiological data from the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) epidemic in 2002 and Middle East Respiratory Syndrome coronavirus (MERS-CoV) epidemic in 2012, are shown. Results: The overall outcomes provided by the software are comforting, as a matter of the fact that IDS has identified with a good accuracy the SARS and MERS epidemics (over 90%), while, as expected, it has not provided erroneous and equivocal readings after the elaboration COVID-19 epidemic data. Conclusions: Even though IDS has not recognized the COVID-19 epidemic, it has not given to the end user a false result and wrong interpretation, as expected by the developers. For this reason, IDS reveals itself as useful software to identify a possible epidemic or outbreak. Thus, the intention of developers is to plan, once the software will be released, dedicated updates and upgrades of the database (e.g., SARS-CoV-2) in order to keep this tool increasingly useful and applicable to reality.

The coronavirus (CoV) infects a broad range of hosts including humans as well as a variety of animals. It has gained overwhelming concerns since the emergence of deadly human coronaviruses (HCoVs), severe acute respiratory syndrome coronavirus (SARS-CoV) in 2003, followed by Middle East respiratory syndrome coronavirus (MERS-CoV) in 2015. Very recently, special attention has been paid to the novel coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 due to its high mobility and mortality. As the COVID-19 pandemic continues, despite vast research efforts, the effective pharmaceutical interventions are still not available for clinical uses. Both expanded knowledge on structure insights and the essential function of viral nucleocapsid (N) protein are key basis for the development of novel, and potentially, a broad-spectrum inhibitor against coronavirus diseases. This review aimed to delineate the current research from the perspective of biochemical and structural study in cell-based assays as well as virtual screen approaches to identify N protein antagonists targeting not only HCoVs but also animal CoVs.

Highlights • Non-severe COVID-19 patients have abnormal laboratory investigations. • Patients with prolonged pretreatment APTT have a longer isolation length. • Patients with elevated eosinophils after treatment have a shorter isolation length. • A nomogram could help to predict isolation probability at 11-, 16- and 21-day., Background Majority coronavirus disease 2019 (COVID-19) patients are classified as mild and moderate (non-severe) diseases. We aim to develop a model to predict isolation length for non-severe patients. Methods Among 188 non-severe patients, 96 patients were enrolled as training cohort to identify factors associated with isolation length via Cox regression model and develop a nomogram. Other 92 patients formed as validation cohort to validate nomogram. Concordance index (C-index), area under the curve (AUC) and calibration curves were used to evaluated nomogram. Results Increasing absolute eosinophil count (AEC) after admission was correlated with shorter isolation length (P = 0.02). Baseline activated partial thromboplastin time (APTT) > 30 s was correlated with longer isolation length (P = 0.03). A nomogram to predict isolation probability at 11-, 16- and 21-day was developed and validated. The C-indices of training and validation cohort were 0.604 and 0.682 respectively. Both cohorts showed a good discriminative ability (AUC, 11-day: 0.646 vs 0.730; 16-day: 0.663 vs 0.750; 21-day: 0.711 vs 0.783; respectively) and calibration power. Conclusions Baseline APTT and dynamic change of AEC were two significant factors associated with isolation length of non-severe patients. Nomogram could predict isolation probability for each patient to estimate appropriate quarantine length.

Sialic acids are nine-carbon sugars that frequently cap glycans at the cell surface in cells of vertebrates as well as cells of certain types of invertebrates and bacteria. The nine-carbon backbone of sialic acids can undergo extensive enzymatic modification in nature and O-acetylation at the C-4/7/8/9 position in particular is widely observed. In recent years, the detection and analysis of O-acetylated sialic acids have advanced, and sialic acid-specific O-acetyltransferases (SOATs) and O-acetylesterases (SIAEs) that add and remove O-acetyl groups, respectively, have been identified and characterized in mammalian cells, invertebrates, bacteria, and viruses. These advances now allow us to draw a more complete picture of the biosynthetic pathway of the diverse O-acetylated sialic acids to drive the generation of genetically and biochemically engineered model cell lines and organisms with altered expression of O-acetylated sialic acids for dissection of their roles in glycoprotein stability, development, and immune recognition, as well as discovery of novel functions. Furthermore, a growing number of studies associate sialic acid O-acetylation with cancer, autoimmunity, and infection, providing rationale for the development of selective probes and inhibitors of SOATs and SIAEs. Here, we discuss the current insights into the biosynthesis and biological functions of O-acetylated sialic acids and review the evidence linking this modification to disease. Furthermore, we discuss emerging strategies for the design, synthesis, and potential application of unnatural Oacetylated sialic acids and inhibitors of SOATs and SIAEs that may enable therapeutic targeting of this versatile sialic acid modification.

Graphical abstract, Safer and more-effective drugs are urgently needed to counter infections with the highly pathogenic SARS-CoV-2, cause of the COVID-19 pandemic. Identification of efficient inhibitors to treat and prevent SARS-CoV-2 infection is a predominant focus. Encouragingly, using X-ray crystal structures of therapeutically relevant drug targets (PLpro, Mpro, RdRp, and S glycoprotein) offers a valuable direction for anti–SARS-CoV-2 drug discovery and lead optimization through direct visualization of interactions. Computational analyses based primarily on MMPBSA calculations have also been proposed for assessing the binding stability of biomolecular structures involving the ligand and receptor. In this study, we focused on state-of-the-art X-ray co-crystal structures of the abovementioned targets complexed with newly identified small-molecule inhibitors (natural products, FDA-approved drugs, candidate drugs, and their analogues) with the assistance of computational analyses to support the precision design and screening of anti–SARS-CoV-2 drugs.

The novel betacoronavirus, SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2), has spread across the globe at an unprecedented rate since its first emergence in Wuhan City, China in December 2019. Scientific communities around the world have been rigorously working to develop a potent vaccine to combat COVID-19 (coronavirus disease 2019), employing conventional and novel vaccine strategies. Gene-based vaccine platforms based on viral vectors, DNA, and RNA, have shown promising results encompassing both humoral and cell-mediated immune responses in previous studies, supporting their implementation for COVID-19 vaccine development. In fact, the U.S. Food and Drug Administration (FDA) recently authorized the emergency use of two RNA-based COVID-19 vaccines. We review current gene-based vaccine candidates proceeding through clinical trials, including their antigenic targets, delivery vehicles, and route of administration. Important features of previous gene-based vaccine developments against other infectious diseases are discussed in guiding the design and development of effective vaccines against COVID-19 and future derivatives., Graphical abstract Unlabelled Image

Graphical abstract, Chemokines are crucial inflammatory mediators needed during an immune response to clear pathogens. However, their excessive release is the main cause of hyperinflammation. In the recent COVID-19 outbreak, chemokines may be the direct cause of acute respiratory disease syndrome, a major complication leading to death in about 40% of severe cases. Several clinical investigations revealed that chemokines are directly involved in the different stages of SARS-CoV-2 infection. Here, we review the role of chemokines and their receptors in COVID-19 pathogenesis to better understand the disease immunopathology which may aid in developing possible therapeutic targets for the infection.

COVID-19 pandemic caused by SARS-CoV-2, continues to manifest with severe acute respiratory syndrome among the adults, however, it offers a convincing indication of less severity and fatality in pediatric age group (0-18 years). The current trend suggests that children may get infected but are less symptomatic with less fatality, which is concordant to earlier epidemic outbreaks of SARS-CoV and MERS-CoV, in 2002 and 2012, respectively. According to the available data, children appear to be at lower risk for COVID-19, as adults constitute for maximum number of the confirmed cases (308,592) and deaths (13,069) as on 22nd March (https://www.worldometers.info/coronavirus). However, rapid publications and information of the adult patients with COVID-19 is in progress and published, on the contrary, almost no comprehensive data or discussion about the COVID-19 in children is available. Therefore, in this review, we outline the epidemiology, clinical symptoms, diagnosis, treatment, prevention, possible immune response and role of thymus in children to combat the COVID-19 outbreak.

Graphical abstract Physiology and pathophysiology of pulmonary alveoli during SARS-CoV-2 infection. (A) COVID-19 severity: frequency of degrees of clinical manifestations in a Chinese cohort (>44.000 patients) (ref: Wu Z. et al, 2020). (B) Phases of COVID-19 disease and timing for the use of glucocorticoids. Legend: ARDS: Adult Respiratory Distress Syndrome; COVID-19: CoronaVirus Disease-19; MOF: multi-organ failure; pts: patients; SIRS: systemic inflammatory response syndrome., Highlights • Dexamethasone reduces the risk of death in patients critically ill with COVID-19. • No evidence of benefit from other complementary and/or supportive treatments was seen in critically ill COVID-19 hospitalized patients. • Synthetic glucocorticoids switch off cytokine storm, and consequent severe respiratory and multi-organ failures in patients with COVID-19. • Effects of synthetic glucocorticoids might be confounded by the contemporary use of other complementary drugs., The viral infection by SARS-CoV-2 has irrevocably altered the life of the majority of human beings, challenging national health systems worldwide, and pushing researchers to rapidly find adequate preventive and treatment strategies. No therapies have been shown effective with the exception of dexamethasone, a glucocorticoid that was recently proved to be the first life-saving drug in this disease. Remarkably, around 20 % of infected people develop a severe form of COVID-19, giving rise to respiratory and multi-organ failures requiring subintensive and intensive care interventions. This phenomenon is due to an excessive immune response that damages pulmonary alveoli, leading to a cytokine and chemokine storm with systemic effects. Indeed glucocorticoids’ role in regulating this immune response is controversial, and they have been used in clinical practice in a variety of countries, even without a previous clear consensus on their evidence-based benefit.

Since December 2019, the COVID-19 pandemic has become a major public health problem. To date, there is no evidence of a higher incidence of COVID in patients with autoimmune rheumatic diseases and we support the approach of maintaining chronic rheumatological treatments. However, once infected there is a small but significant increased risk of mortality. Among the different treatments, NSAIDs are associated with higher rates of complications, but data for other drugs are conflicting or incomplete. The use of certain drugs for autoimmune inflammatory rheumatisms appears to be a potentially interesting options for the treatment. The rationale for their use is based on the immune system runaway and the secretion of pro-inflammatory cytokines (Il1, IL6, TNFα) in severe forms of the disease. Notably, patients on chloroquine or hydroxychloroquine as a treatment for their autoimmune rheumatic disease are not protected from COVID-19., Depuis décembre 2019, la pandémie de COVID-19 est devenue un problème majeur de santé publique. À ce jour, il n’y a aucune preuve d’une incidence plus élevée de COVID chez les patients atteints de maladies rhumatismales auto-immunes et nous soutenons l’approche consistant à maintenir les traitements rhumatologiques chroniques. Cependant, une fois infecté, il y a un risque accru de mortalité faible mais significatif. Parmi les différents traitements, les AINS sont associés à des taux plus élevés de complications, mais les données pour d’autres médicaments sont contradictoires ou incomplètes. L’utilisation de certains médicaments pour les rhumatismes inflammatoires auto-immuns semble être une option potentiellement intéressante pour le traitement. La raison de leur utilisation est basée sur l’emballement du système immunitaire et la sécrétion de cytokines pro-inflammatoires (Il1, IL6, TNFα) dans les formes graves de la maladie. Notamment, les patients sous chloroquine ou hydroxychloroquine comme traitement de leur maladie rhumatismale auto-immune ne sont pas protégés contre la COVID-19.

The emergence of coronavirus disease 2019 (COVID-19) pandemic in Wuhan city, China at the end of 2019 made it urgent to identify the origin of the causal pathogen and its molecular evolution, to appropriately design an effective vaccine. This study analyzes the evolutionary background of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 or SARS-2) in accordance with its close relative SARS-CoV (SARS-1), which was emerged in 2002. A comparative genomic and proteomic study was conducted on SARS-2, SARS-1, and Middle East respiratory syndrome coronavirus (MERS), which was emerged in 2012. In silico analysis inferred the genetic variability among the tested viruses. The SARS-1 genome harbored 11 genes encoding 12 proteins, while SARS-2 genome contained only 10 genes encoding for 10 proteins. MERS genome contained 11 genes encoding 11 proteins. The analysis also revealed a slight variation in the whole genome size of SARS-2 comparing to its siblings resulting from sequential insertions and deletions (indels) throughout the viral genome particularly ORF1AB, spike, ORF10 and ORF8. The effective indels were observed in the gene encoding the spike protein that is responsible for viral attachment to the angiotensin-converting enzyme 2 (ACE2) cell receptor and initiating infection. These indels are responsible for the newly emerging COVID-19 variants αCoV, βCoV, γCoV and δCoV. Nowadays, few effective COVID-19 vaccines developed based on spike (S) glycoprotein were approved and become available worldwide. Currently available vaccines can relatively prevent the spread of COVID-19 and suppress the disease. The traditional (killed or attenuated virus vaccine and antibody-based vaccine) and innovated vaccine production technologies (RNA- and DNA-based vaccines and viral vectors) are summarized in this review. We finally highlight the most common questions related to COVID-19 disease and the benefits of getting vaccinated.

The Middle East respiratory syndrome coronavirus (MERS-CoV), belonging to the family Coronaviridae and genus Betacoronavirus, has been recognized as a highly pathogenic virus. Due to the lack of therapeutic or preventive agents against MERS-CoV, developing an effective vaccine is essential for preventing a viral outbreak. To address this, we developed a recombinant S1 subunit of MERS-CoV spike protein fused with the human IgG4 Fc fragment (LV-MS1-Fc) in Chinese hamster ovary (CHO) cells. Thereafter, we identified the baculovirus gp64 signal peptide-directed secretion of LV-MS1-Fc protein in the extracellular fluid. To demonstrate the immunogenicity of the recombinant LV-MS1-Fc proteins, BALB/c mice were inoculated with 2.5 μg of LV-MS1-Fc. The inoculated mice demonstrated a significant humoral immune response, measured via total IgG and neutralizing antibodies. In addition, human dipeptidyl peptidase-4 (DPP4) transgenic mice vaccinated with LV-MS1-Fc showed the protective capacity of LV-MS1-Fc against MERS-CoV with no inflammatory cell infiltration. These data showed that the S1 and Fc fusion protein induced potent humoral immunity and antigen-specific neutralizing antibodies in mice, and conferred protection against coronavirus viral challenge, indicating that LV-MS1-Fc is an effective vaccine candidate against MERS-CoV infection.

The mRNA therapeutics have been studied since the 1970s and the currently available mRNA vaccines against COVID-19 are the culmination of decades of scientific research. The mRNA vaccines BNT162b2 and mRNA-1273 have played a key role in our global response to the COVID-19 pandemic as they have demonstrated significant advantages over conventional vaccines and have proven to be highly effective against COVID-19 associated hospitalization and severe illness in large clinical trials and studies using real-world data.

In December 2019, a highly transmissible, pneumonia epidemic caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), erupted in China and other countries, resulting in devastation and health crisis worldwide currently. The search and using existing drugs support to curb the current highly contagious viral infection is spirally increasing since the pandemic began. This is based on these drugs had against other related RNA-viruses such as MERS-Cov, and SARS-Cov. Moreover, researchers are scrambling to identify novel drug targets and discover novel therapeutic options to vanquish the current pandemic. Since there is no definitive treatment to control Covid-19 vaccines are remain to be a lifeline. Currently, many vaccine candidates are being developed with most of them are reported to have positive results. Therapeutic targets such as helicases, transmembrane serine protease 2, cathepsin L, cyclin G-associated kinase, adaptor-associated kinase 1, two-pore channel, viral virulence factors, 3-chymotrypsin-like protease, suppression of excessive inflammatory response, inhibition of viral membrane, nucleocapsid, envelope, and accessory proteins, and inhibition of endocytosis were identified as a potential target against COVID-19 infection. This review also summarizes plant-based medicines for the treatment of COVID-19 such as saposhnikoviae divaricata, lonicerae japonicae flos, scutellaria baicalensis, lonicera japonicae, and some others. Thus, this review aimed to focus on the most promising therapeutic targets being repurposed against COVID-19 and viral elements that are used in COVID-19 vaccine candidates.

Aims: At the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, there were no clinically-tested medications for the effective treatment of coronavirus disease. In this context, on 5 March 2020, the French Public Health Council issued several recommendations for the therapeutic management of this new disease, including the use of hydroxychloroquine (HCQ). An unexpected cardiovascular safety signal was quickly identified as being more frequent than expected thanks to the reports of adverse drug reactions (ADRs) submitted to French regional pharmacovigilance centres (RPVC). The objective: of this study was to compare all ADRs reported with HCQ used in its usual indication, collected before the pandemic period (1985 to 31 December, 2019) with those reported with the coronavirus disease 2019 (COVID-19) indication (1 January to 21 July, 2020). Methods: For this purpose, reports were extracted from the French pharmacovigilance database and analysed for these two periods. Results: Our study showed a different safety profile in COVID-19 patients with more cardiac disorders (57% of ADRs versus 5% before the pandemic period), especially QT interval prolongation, resulting from an interaction with azithromycin in more than 20% of cases. Hepatobiliary disorders were also significantly more frequent. Conclusions: These observations could be associated with the effect of the virus itself on the various organs, the profile of the patients treated, and concomitant drug treatments.

Graphical abstract SARS-CoV-2 infected alveoli and the different types of the two antibody-based treatments discussed in this review. Can antibodies be used to protect against COVID-19 and neutralize autoantibodies?, Coronavirus disease 2019 (COVID-19) has been declared by the World Health Organization (WHO) as a pandemic since March 2020. This disease is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The only available tools to avoid contamination and transmission of this virus are physical distancing, the use of N95 and surgical masks, and hand hygiene. Vaccines are another essential tool to reduce the impact of the pandemic, though these present challenges in terms of production and logistics, particularly in underdeveloped and developing countries. One of the critical early research findings is the interaction of the spike virus protein with the angiotensin-converting enzyme 2 (ACE2) human receptor. Developing strategies to block this interaction has therefore been identified as a way to treat this infection. Neutralizing antibodies (nAbs) have emerged as a therapeutic approach since the pandemic started. Infected patients may be asymptomatic or present with mild symptoms, and others may evolve to moderate or severe disease, leading to death. An immunological phenomenon known as cytokine storm has been observed in patients with severe disease characterized by a proinflammatory cytokine cascade response that leads to lung injury. Thus, some treatment strategies focus on anti-cytokine storm nAbs. This review summarizes the latest advances in research and clinical trials, challenges, and perspectives on antibody-based treatments (ABT) as therapies against COVID-19.

Responding quickly to emerging respiratory viruses, such as SARS-CoV-2 the causative agent of coronavirus disease 2019 (COVID-19) pandemic, is essential to stop uncontrolled spread of these pathogens and mitigate their socio-economic impact globally. This can be achieved through drug repurposing, which tackles inherent time- and resource-consuming processes associated with conventional drug discovery and development. In this review, we examine key preclinical and clinical therapeutic and prophylactic approaches that have been applied for treatment of SARS-CoV-2 infection. We break these strategies down into virus- versus host-targeting and discuss their reported efficacy, advantages, and disadvantages. Importantly, we highlight emerging evidence on application of host serine protease-inhibiting anticoagulants, such as nafamostat mesylate, as a potentially powerful therapy to inhibit virus activation and offer cross-protection against multiple strains of coronavirus, lower inflammatory response independent of its antiviral effect, and modulate clotting problems seen in COVID-19 pneumonia.

The goal of the study was to adapt our Middle East respiratory syndrome coronavirus (MERS-CoV) lab-developed test (LDT) to 3 "Sample to Result" (S2R) systems: BD MAX (BD), ELITe InGenius (ELITechGroup), and ARIES (Luminex). The BD MAX and InGenius system allowed use of lab-developed primers and TaqMan probes, while ARIES required conversion to MultiCode primers for melting curve analysis. Each device required ≤1 day of training and assay optimization. No discordant results were noted after analysis of 32 External Quality Control (EQC) samples. On a 10-fold dilution series of a MERS-CoV-positive EQC sample, InGenius obtained the highest detection rate. Laboratory technicians rated the ARIES as the user-friendliest. It also required the least hands-on time. BD MAX had the lowest turnaround time and highest throughput. While each device had distinguishing system properties with associated (dis)advantages, the 3 S2R systems were comparable in terms of assay development and validation. ispartof: DIAGNOSTIC MICROBIOLOGY AND INFECTIOUS DISEASE vol:94 issue:4 pages:349-354 ispartof: location:United States status: published

SARS-CoV-2, as the causative agent of COVID-19, is an enveloped positives-sense single-stranded RNA virus that belongs to the Beta-CoVs sub-family. A sophisticated hyper-inflammatory reaction named cytokine storm is occurred in patients with severe/critical COVID-19, following an imbalance in immune-inflammatory processes and inhibition of antiviral responses by SARS-CoV-2, which leads to pulmonary failure, ARDS, and death. The miRNAs are small non-coding RNAs with an average length of 22 nucleotides which play various roles as one of the main modulators of genes expression and maintenance of immune system homeostasis. Recent evidence has shown that Homo sapiens (hsa)-miRNAs have the potential to work in three pivotal areas including targeting the virus genome, regulating the inflammatory signaling pathways, and reinforcing the production/signaling of IFNs-I. However, it seems that several SARS-CoV-2-induced interfering agents such as viral (v)-miRNAs, cytokine content, competing endogenous RNAs (ceRNAs), etc. preclude efficient function of hsa-miRNAs in severe/critical COVID-19. This subsequently leads to increased virus replication, intense inflammatory processes, and secondary complications development. In this review article, we provide an overview of hsa-miRNAs roles in viral genome targeting, inflammatory pathways modulation, and IFNs responses amplification in severe/critical COVID-19 accompanied by probable interventional factors and their function. Identification and monitoring of these interventional elements can help us in designing the miRNAs-based therapy for the reduction of complications/mortality rate in patients with severe/critical forms of the disease.

SARS-CoV-2 has become a big challenge for the scientific community worldwide. SARS-CoV-2 enters into the host cell by the spike protein binding with an ACE2 receptor present on the host cell. Developing safe and effective inhibitor appears an urgent need to interrupt the binding of SARS-CoV-2 spike protein with ACE2 receptor in order to reduce the SARS-CoV-2 infection. We have examined the penta-peptide ATN-161 as potential inhibitor of ACE2 and SARS-CoV-2 spike protein binding, where ATN-161 has been commercially approved for the safety and possess high affinity and specificity towards the receptor binding domain (RBD) of S1 subunit in SARS-CoV-2 spike protein. We carried out experiments and confirmed these phenomena that the virus bindings were indeed minimized. ATN-161 peptide can be used as an inhibitor of protein-protein interaction (PPI) stands as a crucial interaction in biological systems. The molecular docking finding suggests that the binding energy of the ACE2-spike protein complex is reduced in the presence of ATN-161. Protein-protein docking binding energy (-40.50 kcal/mol) of the spike glycoprotein toward the human ACE2 and binding of ATN-161 at their binding interface reduced the biding energy (-26.25 kcal/mol). The finding of this study suggests that ATN-161 peptide can mask the RBD of the spike protein and be considered as a neutralizing candidate by binding with the ACE2 receptor. Peptide-based masking of spike S1 protein (RBD) and its neutralization is a highly promising strategy to prevent virus penetration into the host cell. Thus masking of the RBD leads to the loss of receptor recognition property which can reduce the chance of infection host cells.

The world is facing on-going challenges due to the spread of the coronavirus SARS-CoV-2, which is affecting the health of people worldwide and the economy of countries. Social distancing, lockdown and quarantine measures have been implemented globally to limit the spread of the virus with a profound impact on people’s lives. These are interventions which are not considered to be permanent and reproducible in the long-term. As more evidence is growing around the airborne transmission routes of the virus, as previously identified for other viruses such as tuberculosis, measles, influenza and coronaviruses, the role of heating, ventilation and air-conditioning (HVAC) systems in buildings, enclosed spaces and public transport in limiting the transmission of airborne pathogens has become a topic of significant relevance. Although the HVAC strategies recommended by professional engineering associations are capable of minimising the transmission of airborne pathogens, they are also responsible for an increase in energy consumption and possibly in a reduction of thermal comfort for occupants. The objective of the study is to review the role of HVAC in airborne viral transmission, to estimate the energy penalty associated with the implementation of the main HVAC strategies for transmission reduction and understand the potential of liquid desiccant technology as an air scrubber. That is capable to a) energy-efficiently control temperature and humidity in buildings, enclosed spaces and public transport; b) increase the indoor air quality by offering the conditions of temperature and humidity less favourable to the growth, proliferation and infectivity of microorganisms; and c) inactivate pathogens. The main factors involved in the process of the inactivation of viruses or pathogens by liquid desiccant solutions are also described together with possible modifications to the solutions to increase their heat and mass transfer and sanitising characteristics. The study is ended by an economic evaluation of the potential energy benefits resulting from the use of liquid desiccant technology. It is concluded that the technology could be particularly favourable in those buildings where humidity control and/or moisture removal is required or in buildings where viruses are more likely to be present, such as in healthcare facilities/operating rooms, or in the event of an airborne viral outbreak.

Objective In this study, we focused on the interaction between SARS-CoV-2 and host Type I Interferon (IFN) response, so as to identify whether IFN effects could be influenced by the products of SARS-CoV-2. Methods All the structural and non-structural proteins of SARS-CoV-2 were transfected and overexpressed in the bronchial epithelial cell line BEAS-2B respectively, and typical antiviral IFN-stimulated gene (ISG) ISG15 expression was detected by qRT-PCR. RNA-seq based transcriptome analysis was performed between control and Spike (S) protein-overexpressed BEAS-2B cells. The expression of ACE2 and IFN effector JAK-STAT signaling activation were detected in control and S protein-overexpressed BEAS-2B cells by qRT-PCR or/and Western blot respectively. The interaction between S protein with STAT1 and STAT2, and the association between JAK1 with downstream STAT1 and STAT2 were measured in BEAS-2B cells by co-immunoprecipitation (co-IP). Results S protein could activate IFN effects and downstream ISGs expression. By transcriptome analysis, overexpression of S protein induced a set of genes expression, including series of ISGs and the SARS-CoV-2 receptor ACE2. Mechanistically, S protein enhanced the association between the upstream JAK1 and downstream STAT1 and STAT2, so as to promote STAT1 and STAT2 phosphorylation and ACE2 expression. Conclusion SARS-CoV-2 S protein enhances ACE2 expression via facilitating IFN effects, which may help its infection.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread around the globe leading to the COVID-19 pandemic. To mitigate the effects of the virus on public health and the global economy, vaccines were rapidly developed. In less than one year, with respect to usual clinical development rules, several vaccines have been put on the market and mass vaccination campaigns have been deployed. During the phase I to phase III clinical trials, most of these vaccines have demonstrated both their safety and efficacy. Despite questions remain about the impact of virus variants and the duration of the immune response, messenger RNA (mRNA)-based and adenoviral vectored vaccines have demonstrated an overall efficacy from 70 to 95% in both phase III trials and real life. In addition, all these vaccines also reduce the severe forms of the disease and might strongly impact the mortality which could change the course of the pandemic.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic that has infected over a hundred million people globally. There have been more than two million deaths recorded worldwide, with no end in sight until a widespread vaccination will be achieved. Current research has centred on different aspects of the virus interaction with cell surface receptors, but more needs to be done to further understand its mechanism of action in order to develop a targeted therapy and a method to control the spread of the virus. Lipids play a crucial role throughout the viral life cycle, and viruses are known to exploit lipid signalling and synthesis to affect host cell lipidome. Emerging studies using untargeted metabolomic and lipidomic approaches are providing new insight into the host response to COVID-19 infection. Indeed, metabolomic and lipidomic approaches have identified numerous circulating lipids that directly correlate to the severity of the disease, making lipid metabolism a potential therapeutic target. Circulating lipids play a key function in the pathogenesis of the virus and exert an inflammatory response. A better knowledge of lipid metabolism in the host-pathogen interaction will provide valuable insights into viral pathogenesis and to the development of novel therapeutic targets.

Graphical abstract, The 2019 novel coronavirus (2019-nCoV; severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) has witnessed a rapid and global proliferation since its early identification in patients with severe pneumonia in Wuhan, China. As of 27th May 2020, 2019-nCoV cases have risen to >5 million, with confirmed deaths of 350,000. However, Coronavirus disease (COVID-19) diagnostic and treatment measures are yet to be fully unraveled, given the novelty of this particular coronavirus. Hence, no drug or vaccine has been adapted for treatment, and the accuracy of the current diagnostic tests is debatable. Therefore, existing antiviral agents used for severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) were repurposed for COVID-19, taking their biological features into consideration. This study provides a concise review of the current and emerging detection and supervision technologies for SARS-CoV-2, which is the viral etiology of COVID19, and their performance characteristics, with emphasis on the novel Nano-based diagnostic tests (protein corona sensor array and magnetic levitation) and treatment measures (treatment protocols based on nano-silver colloids) for COVID-19.

Background Microvascular dysfunction, serum cytokines and chemokines may play important roles in pathophysiology of coronavirus disease 2019 (COVID-19), especially in severe cases. Methods Patients with COVID-19 underwent non-invasive evaluation of systemic endothelium-dependent microvascular reactivity - using laser Doppler perfusion monitoring in the skin of the forearm - coupled to local thermal hyperemia. Maximal microvascular vasodilatation (44 °C thermal plateau phase) was used as endpoint. A multiplex biometric immunoassay was used to assess a panel of 48 serum cytokines and chemokines. Severe COVID-19 (S-COVID) was defined according to WHO criteria, while all other cases of COVID-19 were considered mild to moderate (M-COVID). A group of healthy individuals who tested negative for SARS-CoV-2 served as a control group and was also evaluated with LDPM. Results Thirty-two patients with COVID-19 (25% S-COVID) and 14 controls were included. Basal microvascular flow was similar between M-COVID and controls (P = 0.69) but was higher in S-COVID than in controls (P = 0.005) and M-COVID patients (P = 0.01). The peak microvascular vasodilator response was markedly decreased in both patient groups (M-COVID, P = 0.001; S-COVID, P, Highlights • During acute COVID-19, endothelium-dependent microvascular vasodilator responses are reduced. • Impaired systemic microvascular vasodilation is more evident in severe vs mild-moderate COVID-19. • Increased levels of cytokines and chemokines are associated with COVID-19 severity.

COVID-19 caused by SARS-CoV-2 is an ongoing global pandemic. SARS-CoV-2 affects the human respiratory tract's epithelial cells, leading to a proinflammatory cytokine storm and chronic lung inflammation. With numerous patients dying daily, a vaccine and specific antiviral drug regimens are being explored. Probiotics are live microorganisms with proven beneficial effects on human health. While probiotics as nutritional supplements are long practiced in different cuisines across various countries, the emerging scientific evidence supports the antiviral and general immune-strengthening health effects of the probiotics. Here, we present an overview of the experimental studies published in the last 10 years that provide a scientific basis for unexplored probiotics as a preventive approach to respiratory viral infections. Based on collated insights from these experimental data, we identify promising microbial strains that may serve as lead prophylactic and immune-boosting probiotics in COVID-19 management.

Highlights • SARS-CoV-2 virus was present in the air in the ICU. • Virus may be discharged in aerosol for days after patients test negative. • The finding may be one of the reasons for patients` re-detectable positive. • The clinical guidelines for recovered COVID-19 patients need to be improved., As coronavirus disease 2019 (COVID-19) is spreading worldwide, there have been arguments regarding the aerosol transmission of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Moreover, some re-detectable positive (RP) patients have been reported. However, little attention has been given to the follow-up of recovered patients, and there is no environmental evidence to determine whether these patients continue to shed the virus after they test negative. Therefore, with an objective to test the hypothesis of airborne transmission of SARS-CoV-2, it is necessary to 1) determine whether SARS-CoV-2 particles are present in the indoor air and 2) determine whether recovered patients are still shedding virus, thus providing much-needed environmental evidence for the management of COVID-19 patients during the recovery period. In this study, surface and air samples were collected from an intensive care unit (ICU) containing one ready-for-discharge patient. All surface samples tested negative, but the air samples tested positive for SARS-CoV-2. This implies that SARS-CoV-2 particles may be shed in aerosol form for days after patients test negative. This finding may be one of the reasons for the observation of RP patients; therefore, there is a need for improved clinical and disease management guidelines for recovered COVID-19 patients.

Maturation of the adaptive immune response is typically thought to improve outcome to virus infections. However, long-standing observations of natural infections with old viruses such as Epstein-Barr virus and newer observations of emerging viruses such as severe acute respiratory syndrome coronavirus 2 responsible for COVID-19 suggest that immune immaturity may be beneficial for outcome. Mechanistic studies and studies of patients with inborn errors of immunity have revealed that immune dysregulation reflecting inappropriate antibody and T-cell responses plays a crucial role in causing bystander inflammation and more severe disease. Further evidence supports a role for innate immunity in normally regulating adaptive immune responses. Thus, changes in immune responses that normally occur with age may help explain an apparent protective role of immune immaturity during virus infections.

Highlights • Epidemiological studies conclude diabetes to be a leading comorbidity of COVID-19. • ACE2 polymorphisms in host can influence SARS-CoV-2 susceptibility or resistance. • The in-silico data need to be corroborated with in-vivo results. • Telemedicine can bring a new change in diabetes care., Background Diabetes has been found to be one of the leading comorbidities associated with fatality in COVID-19 patients. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry is facilitated by interaction with Angiotensin Converting Enzyme-2 (ACE2) and possible polymorphisms in ACE2 can be a determining factor in host-viral protein interaction. A significant shift of healthcare towards ‘Telemedicine’ is also on the rise. In this review, the possible effects of ACE2 polymorphisms on SARS-CoV-2 entry along with the escalation of ‘telemedicine’ is discussed. Method An expansive literature search using keywords: “COVID-19”, “SARS-CoV-2”, “diabetes”, “type 2 diabetes’’, “type 1 diabetes”, “ACE2”, “polymorphism”, “DPP4” and “telemedicine” was conducted on Pubmed and EMBASE till 7th August 2020. Result Possible polymorphisms in ACE2 gene can play a role in influencing the virus entry in host body. Telemedicine can bring a new revolution for medical sector. Conclusion COVID-19 severity is more heinous among diabetic population. So far, the in-silico studies involving human ACE2-viral Spike (S) interaction showed inconsistent predictions regarding some SNPs. But without actual in-vivo studies, a holistic understanding can’t be established.

The coronavirus disease 2019 (COVID-19), which emerged in December 2019, continues to be a serious health concern worldwide. There is an urgent need to develop effective drugs and vaccines to control the spread of this disease. In the current study, the main phytochemical compounds of Nigella sativa were screened for their binding affinity for the active site of the RNA-dependent RNA polymerase (RdRp) enzyme of the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). The binding affinity was investigated using molecular docking methods, and the interaction of phytochemicals with the RdRp active site was analyzed and visualized using suitable software. Out of the nine phytochemicals of N. sativa screened in this study, a significant docking score was observed for four compounds, namely α-hederin, dithymoquinone, nigellicine, and nigellidine. Based on the findings of our study, we report that α-hederin, which was found to possess the lowest binding energy (–8.6 kcal/mol) and hence the best binding affinity, is the best inhibitor of RdRp of SARS-CoV-2, among all the compounds screened here. Our results prove that the top four potential phytochemical molecules of N. sativa, especially α-hederin, could be considered for ongoing drug development strategies against SARS-CoV-2. However, further in vitro and in vivo testing are required to confirm the findings of this study.

SARS-CoV-2 is the causative agent of COVID-19. The dimeric form of the viral Mpro is responsible for the cleavage of the viral polyprotein in 11 sites, including its own N and C-terminus. The lack of structural information for intermediary forms of Mpro is a setback for the understanding its self-maturation process. Herein, we used X-ray crystallography combined with biochemical data to characterize multiple forms of SARS-CoV-2 Mpro. For the immature form, we show that extra N-terminal residues caused conformational changes in the positioning of domain-three over the active site, hampering the dimerization and diminishing its activity. We propose that this form preludes the cis and trans-cleavage of N-terminal residues. Using fragment screening, we probe new cavities in this form which can be used to guide therapeutic development. Furthermore, we characterized a serine site-directed mutant of the Mpro bound to its endogenous N and C-terminal residues during dimeric association stage of the maturation process. We suggest this form is a transitional state during the C-terminal trans-cleavage. This data sheds light in the structural modifications of the SARS-CoV-2 main protease during its self-maturation process.

Graphical abstract, Highlights • Prorteases (Mpro and PLpro) are part of the replication machinery of corona virus. • Mpro and PLpro inhibitors may serve as therapeutic weapons against SARS-CoV-2. • An exquisite picture of the recent coronavirus protease inhibitors is provided. • Experimental screening approaches are also highlighted. • Challenges in the development of effective as well as drug like protease inhibitors is also discussed., Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) brutally perils physical and mental health worldwide. Unavailability of effective anti-viral drug rendering global threat of COVID-19 caused by SARS-CoV-2. In this scenario, viral protease enzymes are crucial targets for drug discovery. This extensive study meticulously focused on two viral proteases such as main protease (Mpro) and papain-like protease (PLpro), those are essential for viral replication. This review provides a detail overview of the targets (Mpro and PLpro) from a structural and medicinal chemistry point of view, together with recently reported protease inhibitors. An insight into the challenges in the development of effective as well as drug like protease inhibitors is discussed. Peptidomimetic and/or covalent coronavirus protease inhibitors possessed potent and selective active site inhibition but compromised in pharmacokinetic parameters to be a drug/drug like molecule. Lead optimization of non-peptidomimetic and/or low molecular weight compounds may be a better option for oral delivery. A masterly combination of adequate pharmacokinetic properties with coronavirus protease activity as well as selectivity will provide potential drug candidates in future. This study is a part of our endeavors which surely dictates medicinal chemistry efforts to discover effective anti-viral agent for this devastating disease.

Graphical abstract, SARS-CoV-2 is the pathogen that caused the global COVID-19 outbreak in 2020. Promising progress has been made in developing vaccines and antiviral drugs. Antivirals medicines are necessary complements of vaccines for post-infection treatment. The main protease (Mpro) is an extremely important protease in the reproduction process of coronaviruses which cleaves pp1ab over more than 11 cleavage sites. In this work, two active main protease inhibitors were found via docking-based virtual screening and bioassay. The IC50 of compound VS10 was 0.20 μM, and the IC50 of compound VS12 was 1.89 μM. The finding in this work can be helpful to understand the interactions of main protease and inhibitors. The active candidates could be potential lead compounds for future drug design.

Given the highly polymorphic nature of Human Leukocyte Antigen (HLA) molecules, it is not surprising that they function as key regulators of the host immune response to almost all invading pathogens, including SARS-CoV-2, the etiological agent responsible for the recent COVID-19 pandemic. Several correlations have already been established between the expression of a specific HLA allele/haplotype and susceptibility/progression of SARS-CoV-2 infection and new ones are continuously emerging. Protective and harmful HLA variants have been described in both mild and severe forms of the disease, but considering the huge amount of existing variants, the data gathered in such a brief span of time are to some extent confusing and contradictory. The aim of this mini-review is to provide a snap-shot of the main findings so far collected on the HLA-SARS-CoV-2 interaction, so as to partially untangle this intricate yarn. As key factors in the generation of antigenic peptides to be presented by HLA molecules, ERAP1 and ERAP2 role in SARS-CoV-2 infection will be revised as well.

Graphical abstract, Highlights • The research highlights a novel strategy to block SARS-CoV-2 entry into the host cell. • High-throughput virtual screening identifies ZINC33039472 as a small molecule with favourable drug-like properties. • It shows higher binding affinity to the spike RBD interface region compared to emodin. • ZINC33039472 could be a potential drug candidate molecule for COVID-19., Coronavirus disease 2019 (COVID-19) is a fatal infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The virus infection is initiated upon recognition and binding of the spike (S) protein receptor-binding domain (RBD) to the host cell surface receptor, angiotensin-converting enzyme 2 (ACE2). Blocking the interaction between S protein and ACE2 receptor is a novel approach to prevent the viral entry into the host cell. The present study is aimed at the identification of small molecules which can disrupt the interaction between SARS-CoV-2 S protein and human ACE2 receptor by binding to the interface region. A chemical library consisting of 1,36,191 molecules were screened for drug-like compounds based on Lipinski’s rule of five, Verber’s rule and in silico toxicity parameters. The filtered drug-like molecules were next subjected to molecular docking in the interface region of RBD. The best three hits viz; ZINC64023823, ZINC33039472 and ZINC00991597 were further taken for molecular dynamics (MD) simulation studies and binding free energy evaluations using Molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) and Molecular mechanics-Generalized Born surface area (MM-GBSA). The protein-ligand complexes showed stable trajectories throughout the simulation time. ZINC33039472 exhibited binding free energy value lower as compared to the control (emodin) with a higher contribution by gas-phase energy and van der Waals energy to the total binding free energy. Thus, ZINC33039472 is identified to be a promising interfacial binding molecule which can inhibit the interaction between the viral S protein and human ACE2 receptor which would consequently help in the management of the disease.

SARS-COV-2 infection represents the greatest pandemic of the world, counting daily increasing number of subjects positive to the virus and, sadly, increasing number of deaths. Current studies reported that the cytokine/chemokine network is crucial in the onset and maintenance of the "cytokine storm", the event occurring in those patients in whom the progression of COVID-19 will progress, in most cases, to a very severe and potentially threatening disease. Detecting a possible "immune signature" in patients, as assessed by chemokines status in patients with COVID-19, could be helpful for individual risk stratification for developing a more or less severe clinical course of the disease. The present review is specifically aimed at overviewing current evidences provided by in vitro and in vivo studies addressing the issue of which chemokines seems to be involved, at least at present, in COVID-19. Currently available experimental and clinical studies regarding those chemokines more deeply studied in COVID-19, with a specific focus on their role in the cytokine storm and ultimately with their ability to predict the clinical course of the disease, will be taken into account. Moreover, similarities and differences between chemokines and cytokines, which both contribute to the onset of the pro-inflammatory loop characterizing SARS-COV-2 infection, will be briefly discussed. Future studies will rapidly accumulate in the next months and their results will hopefully provide more insights as to the complex physiopathology of COVID-19-related cytokine storm. This will likely make the present review somehow "dated" in a short time, but still the present review provides an overview of the scenario of the current knowledge on this topic.

Graphical abstract, Highlights • Plant extracts are a source of phytochemicals useful in the treatment of coronavirus diseases. • The advantage of using natural plant extracts is their effectiveness and high safety for patients. • Water and ethanol plant extracts contain biologically active substances with antiviral activity. • Phytochemicals are natural inhibitors of viral enzymes., The outbreak of Covid-19 disease caused by SARS-CoV-19, along with the lack of targeted medicaments and vaccines, forced the scientific world to search for new antiviral formulations. In this review, we describe the current knowledge about plant extracts containing polyphenols that inhibit Covid-19. Many plant-derived natural compounds (polyphenols) might provide a starting point for the research on the use of plant extracts in coronavirus treatment and prevention. Antivirus polyphenolic drugs can inhibit coronavirus enzymes, which are essential for virus replication and infection. This group of natural substances (betulinic acid, indigo, aloeemodine, luteolin, and quinomethyl triterpenoids, quercitin or gallates) is a potential key to designing antiviral therapies for inhibiting viral proteases. The known pharmacophore structures of bioactive substances can be useful in the elaboration of new anti-Covid-19 formulations. The benefit of using preparations containing phytochemicals is their high safety for patients and no side effects.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first discovered in December 2019 in Wuhan, China, and expeditiously spread across the globe causing a global pandemic. Research on SARS-CoV-2, as well as the closely related SARS-CoV-1 and MERS coronaviruses, is restricted to BSL-3 facilities. Such BSL-3 classification makes SARS-CoV-2 research inaccessible to the majority of functioning research laboratories in the United States; this becomes problematic when the collective scientific effort needs to be focused on such in the face of a pandemic. However, a minimal system capable of recapitulating different steps of the viral life cycle without using the virus’ genetic material could increase accessibility. In this work, we assessed the four structural proteins from SARS-CoV-2 for their ability to form virus-like particles (VLPs) from human cells to form a competent system for BSL-2 studies of SARS-CoV-2. Herein, we provide methods and resources of producing, purifying, fluorescently and APEX2-labeling of SARS-CoV-2 VLPs for the evaluation of mechanisms of viral budding and entry as well as assessment of drug inhibitors under BSL-2 conditions. These systems should be useful to those looking to circumvent BSL-3 work with SARS-CoV-2 yet study the mechanisms by which SARS-CoV-2 enters and exits human cells.