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The spread of SARS-CoV-2 keeps threatening human life and health, and small-molecule antivirals are in demand. The main protease (M

Human immunodeficiency virus (HIV) capsid (CA) protein is a promising target for developing novel anti-HIV drugs. Starting from highly anticipated CA inhibitors PF-74, we used scaffold hopping strategy to design a series of novel 1,2,4-triazole phenylalanine derivatives by targeting an unexplored region composed of residues 106-109 in HIV-1 CA hexamer. Compound d19 displayed excellent antiretroviral potency against HIV-1 and HIV-2 strains with EC

Objectives This study was performed to investigate the short-term and long-term survival of patients who underwent reoperative tricuspid valve replacement (TVR). Methods A retrospective analysis was performed of 273 patients who underwent TVRs while hospitalised in Beijing Anzhen Hospital from November 1993 to August 2018. Fifty-six (56) of them underwent reoperative TVR: 36 had previous tricuspid valve repair and 20 had previous TVR. Follow-up was 100% complete, with a mean follow-up of 8 years (range, 1–15 years). Results The overall in-hospital mortality was 17.9% (n=10). In the univariate analysis, the overall in-hospital mortality and renal failure rate in the replacement group were lower than those in the repair group (5.0% vs 25%; p=0.046 and 27.8% vs 5%; p=0.040). However, in-hospital mortality was no longer statistically significant after multivariate adjustment (adjusted OR, 0.318; 95% CI, 0.030–3.338; p=0.340). There was no significant difference in survival between the patients with previous repair and those with previous replacement (log-rank test, p=0.839). Factors that correlated with long-term mortality on multivariate analysis were age >60 years (adjusted HR, 11.753; 95% CI, 1.686–81.915; p=0.013); cardiopulmonary bypass time (adjusted HR, 1.019; 95% CI, 1.005–1.034; p=0.009); intensive care unit time (adjusted HR, 1.024; 95% CI, 1.006–1.042; p=0.009); and ventilation time (adjusted HR, 0.982; 95% CI, 0.965–0.998; p=0.030). Conclusions Reoperative TVR was associated with high in-hospital mortality and morbidity. Overall in-hospital mortality was similar between the previous replacement group and the previous repair group. Previous tricuspid valve repair and replacement had similar long-term survival.

Lesinurad is a uricosuric agent for the treatment of hyperuricemia associated with gout, which was found lacking in efficacy and safety. Here, scaffold hopping and molecular hybridization were exploited to modify all the structural components of lesinurad, and 36 novel compounds bearing bicyclic imidazolopyridine core were obtained. In a mouse model of acute hyperuricemia, 29 compounds demonstrated increased serum uric acid (SUA)-reducing activity; SUA was treated with

As a highly pathogenic human coronavirus, SARS-CoV-2 has to counteract an intricate network of antiviral host responses to establish infection and spread. The nucleic acid-induced stress response is an essential component of antiviral defense and is closely related to antiviral innate immunity. However, whether SARS-CoV-2 regulates the stress response pathway to achieve immune evasion remains elusive. In this study, SARS-CoV-2 NSP5 and N protein were found to attenuate antiviral stress granule (avSG) formation. Moreover, NSP5 and N suppressed IFN expression induced by infection of Sendai virus or transfection of a synthetic mimic of dsRNA, poly (I:C), inhibiting TBK1 and IRF3 phosphorylation, and restraining the nuclear translocalization of IRF3. Furthermore, HEK293T cells with ectopic expression of NSP5 or N protein were less resistant to vesicular stomatitis virus infection. Mechanistically, NSP5 suppressed avSG formation and disrupted RIG-I–MAVS complex to attenuate the RIG-I–mediated antiviral immunity. In contrast to the multiple targets of NSP5, the N protein specifically targeted cofactors upstream of RIG-I. The N protein interacted with G3BP1 to prevent avSG formation and to keep the cofactors G3BP1 and PACT from activating RIG-I. Additionally, the N protein also affected the recognition of dsRNA by RIG-I. This study revealed the intimate correlation between SARS-CoV-2, the stress response, and innate antiviral immunity, shedding light on the pathogenic mechanism of COVID-19.

The Coronavirus Disease 2019 (COVID-19) and dengue fever (DF) pandemics both remain to be significant public health concerns in the foreseeable future. Anti-SARS-CoV-2 drugs and vaccines are both indispensable to eliminate the epidemic situation. Here, two piperazine-based polyphenol derivatives DF-47 and DF-51 were identified as potential inhibitors directly blocking the active site of SARS-CoV-2 and DENV RdRp. Data through RdRp inhibition screening of an in-house library and in vitro antiviral study selected DF-47 and DF-51 as effective inhibitors of SARS-CoV-2/DENV polymerase. Moreover, in silico simulation revealed stable binding modes between the DF-47/DF-51 and SARS-CoV-2/DENV RdRp, respectively, including chelating with Mg2+ near polymerase active site. This work discovered the inhibitory effect of two polyphenols on distinct viral RdRp, which are expected to be developed into broad-spectrum, non-nucleoside RdRp inhibitors with new scaffold. ispartof: MOLECULES vol:28 issue:1 ispartof: location:Switzerland status: published

Secondary hyperparathyroidism (SHPT) is common in dialysis patients with end-stage renal disease (ESRD). Parathyroidectomy (PTX) is an effective treatment for SHPT. Postoperative severe hypocalcemia (SH) is a common and severe complication after PTX. This study aimed to investigate the potential predictive markers of SH in dialysis ESRD patients with SHPT after near-total PTX (near-tPTX) without autotransplantation (AT).A retrospective analysis involving 131 dialysis patients with SHPT who were treated with near-tPTX without AT between January and August 2018 was performed. Demographic characteristics (age, gender, type of dialysis modality, etc.) and perioperative laboratory parameters [serum calcium, phosphorus, alkaline phosphatase (ALP), intact parathyroid hormone (iPTH), and bone metabolism markers] were collected and analyzed. Postoperative serum calcium level1.875 mmol/L (7.5 mg/dL) was defined as postoperative SH.Among the 131 patients, 73 (55.7%) had postoperative hypocalcemia and 43 (32.8%) had postoperative SH. Univariate analysis showed that values of preoperative serum iPTH, calcium, ALP, bone-specific alkaline phosphatase (BAP), and osteocalcin (OC) were significantly different between the SH and non-SH groups. In the multivariate logistic regression model, preoperative serum ALP was an independent risk predictor of postoperative SH. The receiver operating characteristic (ROC) curve for preoperative serum ALP was 277 U/L. The sensitivity of preoperative serum ALP was 73.8% and the specificity was 63.2%.The incidence rates of postoperative hypocalcemia and SH in dialysis patients with SHPT after near-tPTX without AT were 55.7% and 32.8%, respectively. Preoperative serum ALP was an independent predictor for the occurrence of postoperative SH, and dialysis patients with SHPT were susceptible to postoperative SH when preoperative serum ALP level was277 U/L. Hence, we recommend that preoperative serum ALP be utilized to complement clinical protocols for postoperative SH management of dialysis ESRD patients with SHPT after near-tPTX without AT.

HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) area key component of the current HIV-1 combination drug regimens. Although they exhibit potent anti-HIV-1 activity and modest toxicity, the emergence of mutant strains limits their application in clinical. Our previous research efforts contributed to the identification of compound K-5a2, which exhibits nanomolar activity in HIV-1-infected MT-4 cells. In this study, K-5a2 was shown to have a high level of anti-HIV-1 activity against various lab-adapted strains and clinical isolate strains, being comparable to ETR. Moreover, we showed the feasibility of K-5a2 as a preclinical anti-HIV-1 candidate by establishing its synergistic or additive anti-HIV-1 activity in combination with other representative anti-HIV-1 drugs and candidates. In addition, K-5a2 exhibited no inhibitory activity to the primary CYP isoforms and favorable pharmacokinetics. Taken together, its robust anti-HIV-1 potency, synergistic or additive effects with other anti-HIV drugs, and favorable pharmacokinetic and safety profiles make K-5a2 a potent alternative drug for HIV/AIDS treatment.

The continuous spread of SARS-CoV-2 calls for more direct-acting antiviral agents to combat the highly infectious variants. The main protease (M

Urate Transporter 1 (URAT1) plays a crucial role in uric acid transport, making it an attractive target for the treatment of gout and hyperuricemia. As a representative URAT1 inhibitor, Lesinurad treat gout by promoting the uric acid excretion. However, its lower in vitro and in vivo activity should be highly attracted attention. Herein, the bioisosterism, molecular hybridization and scaffold hopping strategies were exploited to modify all the structural components of Lesinurad and finally thirty novel compounds bearing thienopyrimidinone or pyridine core were obtained. Most of the compounds displayed certain URAT1 inhibitory activity in vitro. Among them, thienopyrimidinones 6 (IC

With our continuous endeavors in seeking neuraminidase (NA) inhibitors, we reported herein three series of novel oseltamivir amino derivatives with the goal of exploring the druggable chemical space inside the 150-cavity of influenza virus NAs. Among them, around half of the compounds in

Oxidative stress has a key role in brain injury and melatonin possesses antioxidant effects. We aimed to ascertain the potential relationship between serum melatonin concentrations and functional outcome following aneurysmal subarachnoid hemorrhage (aSAH).This prospective and observational study was conducted of 169 aSAH patients. Baseline serum melatonin concentrations were determined. A worse 6-month functional outcome was defined as a Glasgow Outcome Scale score of 1-3.Patients with a worse outcome (56 cases) compared to those with a good outcome (113 cases) exhibited significantly higher concentrations of serum melatonin (P 0.001). An area under the receiver operating curve of 0.819 was revealed for the prediction of 6-month worse outcome by serum melatonin concentrations. Multiple logistic regression analysis showed an independent association of serum melatonin concentrations with 6-month worse outcome (odds ratio = 1.204). An intimate correlation existed between serum melatonin concentrations and World Federation of Neurological Surgeons subarachnoid hemorrhage scale scores as well as between serum melatonin concentrations and modified Fisher scores (P 0.001).Patients with higher serum melatonin concentrations are more likely to have a poor prognosis. Serum melatonin can be considered as an independent predictor of functional outcome after aSAH.

BackgroundChina's uneven development under the urban-rural dichotomy has led to the discouraging development of children in rural areas. China is a large agricultural country and agricultural disasters are relatively common. Rural children aged 10–15 whose families depend on the agricultural economy may experience far-reaching negative effects from these disasters.ObjectiveThis study explored the effects of agricultural disasters on rural children's development, including cognitive and noncognitive skills, and academic pressure.MethodsSurvey data from the China Family Panel Survey and the National Meteorological Administration for 2010–2018 and a fixed-effect panel model with difference-in-differences regressions were used in the study.ResultsThe fixed effects model results showed evidence that agricultural disasters have a negative impact on rural children's cognitive and noncognitive skills and a positive impact on academic pressure. The statistically significant coefficients are −0.092, −0.938, and 0.223, respectively. School and family environments also explain children's development. Robustness tests confirmed these results.ConclusionsEvidence shows that agricultural disasters have a significant negative impact on rural child development. It may be inferred that these will increase the difficulty of narrowing the urban-rural development gap. China is committed to promoting prosperity for all its people. Special attention should be paid to the consequences of disasters at the child level and appropriate measures should be taken to mitigate possible negative impacts.

Background The prognosis of hepatocellular carcinoma (HCC) varies considerably among patients with the same disease stage and characteristics, and only about two thirds show high levels of α-fetoprotein (AFP), a common prognostic indicator for HCC. Here, we assessed whether the combination of presurgical serum levels of AFP and carbohydrate antigen 19-9 (CA19-9) can predict the prognosis of HCC patients after hepatectomy. Methods The clinicopathological characteristics and post-hepatectomy outcomes of 711 HCC patients were retrospectively reviewed. The patients were classified into three groups based on whether their preoperative serum levels of both AFP and CA19-9 were higher than the respective cut-offs of 400 ng/ml and 37 U/ml [double positive (DP)], the level of only one marker was higher than the cut-off [single positive (SP)], or neither level was higher than the cut-off [negative (N)]. The overall survival (OS) and recurrence-free survival (RFS) rates were estimated using Kaplan–Meier curves. Univariate and multivariate survival analyses were performed to identify the clinicopathological factors significantly associated with HCC prognosis. Results The 1-year, 3-year, and 5-year RFS and OS rates in the N group were significantly higher than those in the SP group, while the DP group showed the lowest rates. Multivariate Cox regression analysis showed that large tumor size (> 5 cm), multiple tumors (≥ 2), incomplete tumor capsule, positive microvascular invasion, Barcelona Clinic Liver Cancer C stage, and CA19-9 level > 37 U/mL were independent risk factors for RFS and OS in HCC patients. Moreover, aspartate aminotransferase levels > 40 U/L proved to be an independent prognostic factor for OS. Conclusion The combination of serum AFP and CA19-9 levels may be a useful prognostic marker for HCC patients after hepatectomy.

Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with a rising incidence worldwide. The prognosis of HCC patients after radical resection remains poor. Radiomics is a novel machine learning method that extracts quantitative features from medical images and provides predictive information of cancer, which can assist with cancer diagnosis, therapeutic decision-making and prognosis improvement.To develop and validate a contrast-enhanced computed tomography-based radiomics model for predicting the overall survival (OS) of HCC patients after radical hepatectomy.A total of 150 HCC patients were randomly divided into a training cohort (In total, seven radiomics features were selected to construct the radiomics signature. According to the results of univariate and multivariate Cox regression analyses, alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR) and radiomics signature were included to build the nomogram. The C-indices of the nomogram in the training and validation cohorts were 0.736 and 0.774, respectively. ROC curve analysis for predicting 1-, 3-, and 5-year OS confirmed satisfactory accuracy [training cohort, area under the curve (AUC) = 0.850, 0.791 and 0.823, respectively; validation cohort, AUC = 0.905, 0.884 and 0.911, respectively]. The calibration curve analysis indicated a good agreement between the nomogram-prediction and actual survival. DCA curves suggested that the nomogram had more benefit than traditional staging system models. Kaplan-Meier survival analysis indicated that patients in the low-risk group had longer OS and disease-free survival (allThe nomogram containing the radiomics signature, NLR and AFP is a reliable tool for predicting the OS of HCC patients.

Taking the previously reported compound BH-7d as the lead, we designed and synthesized a series of piperidinyl-substituted [1,2,4]triazolo[1,5-a]pyrimidines, and their anti-HIV activities as well as cytotoxicities were evaluated. Several compounds exhibited moderate anti-HIV (IIIB) potency, among which 2b was the most active one (EC50 = 4.29 μM). Structure-activity relationships derived from the antiretroviral results were analyzed. Additionally, most compounds demonstrated reduced cytotoxicity (CC50 > 200 μM) compared with those of BH-7d and etravirine. Molecular docking study further revealed the binding conformation of 2b in the binding pocket of HIV-1 reverse transcriptase. ispartof: CHEMICAL BIOLOGY & DRUG DESIGN vol:97 issue:1 pages:67-76 ispartof: location:England status: published

In continuation of our efforts toward the discovery of potent non-nucleoside hepatitis B virus (HBV) inhibitors with novel structures, we have explored the solvent-exposed protein region of heteroaryldihydropyrimidine derivatives. Herein, the morpholine ring of GLS4 was replaced with substituted sulfonamides and triazoles to generate novel non-nucleoside HBV inhibitors with desirable potency. In in vitro biological evaluation, several derivatives showed good anti-HBV DNA replication activity compared to lamivudine. In particular, compound II-1 displayed the most potent activity against HBV DNA replication (IC50 = 0.35 ± 0.04 μM). The preliminary structure-activity relationships of the new compounds were summarized, which may help in discovering more potent anti-HBV agents via rational drug design.

The development of efficacious NNRTIs for AIDS therapy commonly encountered the rapid generation of drug-resistant mutations, which becomes a major impediment to effective anti-HIV treatment. Using a structure-based bioisosterism strategy, a series of piperidine-substituted thiophene[2,3-d]pyrimidine derivatives were designed and synthesized. Compound 9a yielded the greatest potency, exhibiting significantly better anti-HIV-1 activity than ETR against all of the tested NNRTI-resistant HIV-1 strains. In addition, the phenotypic (cross)resistance of 9a and other NRTIs to the different selected HIV-1 strains was evaluated. As expected, no phenotypic cross-resistance against the NRTIs (AZT and PMPA) was observed with the mutant 9ares strain. Furthermore, 9a was identified with improved solubility, lower CYP liability, and hERG inhibition. Remarkably, 9a exhibited optimal pharmacokinetic properties in rats (F = 37.06%) and safety in mice (LD50 > 2000 mg/kg), which highlights 9a as a promising anti-HIV-1 drug candidate.

Our previous efforts have led to the development of two potent NNRTIs, K-5a2 and 25a, exhibiting effective anti-HIV-1 potency and resistance profiles compared with etravirine. However, both inhibitors suffered from potent hERG inhibition and short half-life. In this article, with K-5a2 and etravirine as leads, series of novel fluorine-substituted diarylpyrimidine derivatives were designed via molecular hybridization and bioisosterism strategies. The results indicated 24b was the most active inhibitor, exhibiting broad-spectrum activity (EC50 = 3.60-21.5 nM) against resistant strains, significantly lower cytotoxicity (CC50= 155 μM), and reduced hERG inhibition (IC50 > 30 μM). Crystallographic studies confirmed the binding of 24b and the role of the fluorine atom, as well as optimal contacts of a nitrile group with the main-chain carbonyl group of H235. Furthermore, 24b showed longer half-life and favorable safety properties. All the results demonstrated that 24b has significant promise in circumventing drug resistance as an anti-HIV-1 candidate. ispartof: JOURNAL OF MEDICINAL CHEMISTRY vol:63 issue:3 pages:1298-1312 ispartof: location:United States status: published

Currently, HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are a major component of the highly active anti-retroviral therapy (HAART) regimen. However, the occurrence of drug-resistant strains and adverse reactions after long-term usage have inevitably compromised the clinical application of NNRTIs. Therefore, the development of novel inhibitors with distinct anti-resistance profiles and better pharmacological properties is still an enormous challenge. Herein, we summarize state-of-the-art medicinal chemistry strategies for the discovery of potent NNRTIs, such as structure-based design strategies, contemporary computer-aided drug design, covalent-binding strategies, and the application of multi-target-directed ligands. The strategies described here will facilitate the identification of promising HIV-1 NNRTIs.

Capsid assembly modulators (CAMs) represent a novel class of antiviral agents targeting hepatitis B virus (HBV) capsid to disrupt the assembly process. NVR 3-778 is the first CAM to demonstrate antiviral activity in patients infected with HBV. However, the relatively low aqueous solubility and moderate activity in the human body halted further development of NVR 3-778. To improve the anti-HBV activity and the drug-like properties of NVR 3-778, we designed and synthesized a series of NVR 3-778 derivatives. Notably, phenylboronic acid-bearing compound 7b (EC

Two series of new pyridyl-bearing fused bicyclic analogues designed to target the dual-tolerant regions of the non-nucleoside reverse transcriptase inhibitor (NNRTI)-binding pocket were synthesized and evaluated for their anti-HIV activities. Several compounds, such as 6, 14, 15, 21, 30, and 33, were found to be potent inhibitors against the wild-type (WT) HIV-1 strain or multiple NNRTI-resistant strains at low nanomolar levels. Detailed structure-activity relationships were obtained by utilizing the variation of moieties within the corresponding pharmacophores. In vitro metabolic stability profiles and some drug-like properties of selected compounds were assessed, furnishing the preliminary structure-metabolic stability relationships. Furthermore, molecular modeling studies elucidated the binding modes of compounds 6, 15, 21, and 30 in the binding pocket of WT, E138K, K103N, or Y181C HIV-1 RTs. These promising compounds can be used as lead compounds and warrant further structural optimization to yield more active HIV-1 inhibitors.

The AIDS pandemic is still of importance. HIV-1 and HIV-2 are the causative agents of this pandemic, and in the absence of a viable vaccine, drugs are continually required to provide quality of life for infected patients. The HIV capsid (CA) protein performs critical functions in the life cycle of HIV-1 and HIV-2, is broadly conserved across major strains and subtypes, and is underexploited. Therefore, it has become a therapeutic target of interest. Here, we report a novel series of 2-pyridone-bearing phenylalanine derivatives as HIV capsid modulators. Compound FTC-2 is the most potent anti-HIV-1 compound in the new series of compounds, with acceptable cytotoxicity in MT-4 cells (selectivity index HIV-1 > 49.57; HIV-2 > 17.08). However, compound TD-1a has the lowest EC50 in the anti-HIV-2 assays (EC50 = 4.86 ± 1.71 μM; CC50= 86.54 ± 29.24 μM). A water solubility test found that TD-1a showed a moderately increased water solubility compared with PF74, while the water solubility of FTC-2 was improved hundreds of times. Furthermore, we use molecular simulation studies to provide insight into the molecular contacts between the new compounds and HIV CA. We also computationally predict drug-like properties and metabolic stability for FTC-2 and TD-1a. Based on this analysis, TD-1a is predicted to have improved drug-like properties and metabolic stability over PF74. This study increases the repertoire of CA modulators and has important implications for developing anti-HIV agents with novel mechanisms, especially those that inhibit the often overlooked HIV-2. ispartof: MOLECULES vol:27 issue:21 ispartof: location:Switzerland status: published

Male infertility is a multifactorial condition that is closely associated with chromosomal abnormalities. Reciprocal chromosomal translocation (RCT) is a significant structural genetic abnormality. The specific mechanisms of forms of RCT affecting male infertility include the product of chromosomally unbalanced gametes, thereby disrupting the structure and function of important genes responsible for spermatogenesis. RCT breakpoints have been found to disrupt gene structure and function in many medical fields However, the relationship between RCT breakpoints and male infertility remains to be determined. The purpose of this study is to describe 2 male carriers of RCTs 46,XY,t(8;22)(q13;q13) and 46,XY,t(8;14)(q13;q22). Both patients were collected from the second hospital of Jilin University. Semen parameters were detected using the computer-aided semen analysis system. Cytogenetic analysis was performed using standard operating procedure. Related genes on chromosomal breakpoints were searched using Online Mendelian Inheritance in Man. One man had semen parameters within the normal range, but the couple was infertile after 5 years of marriage. The other man showed normal semen parameters, and his wife had experienced 2 spontaneous miscarriages. Using a literature search, the association between chromosome 22q13 breakpoint and fertility were investigated. The results suggest that physicians should focus on the clinical phenotype of the patients and the breakpoints of RCT in genetic counseling. An important gene related to human male infertility is clearly located in chromosome region 22q13, and its function is worthy of further study.

Human immunodeficiency virus (HIV) reverse transcriptase (RT)-associated ribonuclease H (RNase H) remains as the only enzyme encoded within the viral genome not clinically validated as an antiviral target. We have previously reported that the galloyl derivative II-25 had RNase H inhibitory activity in enzymatic assays but showed weak antiviral activity in phenotypic assays due its large polarity and poor membrane permeability. In this report, we report on a series of II-25 derivatives, obtained by addition of different hydrophobic moieties ("the wings") at the C-2 and C-3 positions of the piperazine ring that showed improved RNase H inhibitory activity. Six compounds showed strong inhibitory activity and were found to be more potent than β-thujaplicinol in enzymatic assays. The most potent compound was IA-6 and exhibited the best inhibitory activity (IC50 = 0.067 ± 0.02 μM). IA-6 was around 11 and 30 times more potent than II-25 and β-thujaplicinol, respectively. Molecular modeling studies predict a strong hydrophobic interaction between the furylmethylaminyl group of IA-6 and the side chain of His539, explaining the potent HIV-1 RNase H inhibition. Unfortunately, none of the derivatives showed significant antiviral activity in cell culture. It is worth emphasizing that most of the obtained compounds show low cytotoxicity (CC50 > 20 μM), which confirms the significance of identifying galloyl derivatives as valuable leads for further optimization., We gratefully acknowledge financial support from the National Natural Science Foundation of China (NSFC Nos. 82173677, 81773574), the Key Project of NSFC for International Cooperation (No. 81420108027), the Shandong Provincial Key Research and Development Project (No. 2019JZZY021011), and the Science Foundation for Outstanding Young Scholars of Shandong Province (ZR2020JQ31). This work was supported in part by the Ministry of Science and Innovation of Spain through grant PID2019-104176RB-I00/AEI/10.13039/501100011 033 awarded to L.M.-A. J.M.R. is a predoctoral fellow of the Spanish Ministry of Universities (Formación de Profesorado Universitario, FPU19/01653). An institutional grant of the Fundación Ramón Areces to the CBMSO is also acknowledged.

Chromosomal aberrations in peripheral blood are a major cause of reproductive disorders for the infertile couples. Reciprocal translocation is closely related to male infertility. The breakpoint of translocation may disrupt or dysregulate important genes related to spermatogenesis. The relationship between some breakpoints of chromosome and male infertility has been paid attention. Chromosome 22q11.2 translocation has not been reported with male infertility. The purpose of this study is to evaluate the relationship between chromosome 22q11.2 translocation and male infertility. All patients were collected from the second hospital of Jilin University. Semen parameters were detected using the computer-aided semen analysis system. Cytogenetic analysis was performed using standard operating procedure. Related genes on chromosomal breakpoints were searched using online mendelian inheritance in man (OMIM). The association between this breakpoint and spermatogenesis is also discussed. We report 6 cases of translocation in chromosome 22. Of 7 breakpoints involved in these translocations, the common feature is that they all included chromosome 22q11.2 translocation and presented with oligozoospermia. The analysis of breakpoint related genes showed testis-specific serine/threonine kinase 2 (TSSK2) gene is associated with human spermatogenesis impairment. Overall, these results suggest that the breakpoint involved in translocation deserves attention from physicians in genetic counseling. The breakpoint rearrangement has the possibility of disrupting spermatogenesis. The relationship between 22q11.2 breakpoint and male infertility deserves further study.

Enlightened by the available structural biology information, a novel series of dihydrothiopyrano[4,3

Recent coronavirus outbreaks of SARS-CoV-1 (2002-2003), MERS-CoV (since 2012), and SARS-CoV-2 (since the end of 2019) are examples of how viruses can damage health care and generate havoc all over the world. Coronavirus can spread quickly from person to person causing high morbidity and mortality. Unfortunately, the antiviral armamentarium is insufficient to fight these infections. In this chapter, we provide a detailed summary of the current situation in the development of drugs directed against pandemic human coronaviruses. Apart from the recently licensed remdesivir, other antiviral agents discussed in this review include molecules targeting viral components (e.g., RNA polymerase inhibitors, entry inhibitors, or protease inhibitors), compounds interfering with virus-host interactions, and drugs identified in large screening assays, effective against coronavirus replication, but with an uncertain mechanism of action.

Breast cancer (BC) is a common type of tumor. Numerous patients are diagnosed and treated in the early stages of the disease; however, the recurrence rate remains high. Therefore, identifying sensitive and specific tumor markers to prevent and treat BC is essential. c‑Myc promoter binding protein 1 (MBP1) is a regulatory molecule located in the cell nucleus. It targets and regulates the expression of various cell proliferation‑, apoptosis‑ and tumor‑associated genes. MBP1 expression in BC tissues was detected using immunohistochemistry and further validated in BC and normal human cell lines using RT‑qPCR and western blot analysis. Low MBP1 expression, in clinical samples of BC, was associated with a poor prognosis of BC (n=50). MBP1 overexpression effectively inhibited the growth and metastasis of xenograft tumors

The HIV-1 Capsid (CA) is considered as a promising target for the development of potent antiviral drugs, due to its multiple roles during the viral life cycle. Herein, we report the design, synthesis, and antiviral activity evaluation of series of novel phenylalanine derivatives as HIV-1 CA protein inhibitors. Among them, 4-methoxy-N-methylaniline substituted phenylalanine (II-13c) and indolin-5-amine substituted phenylalanine (V-25i) displayed exceptional anti-HIV-1 activity with the EC50 value of 5.14 and 2.57 μM respectively, which is slightly weaker than that of lead compound PF-74 (EC50 = 0.42 μM). Besides, surface plasmon resonance (SPR) binding assay demonstrated II-13c and V-25i prefer to combine with CA hexamer rather than monomer, which is similar to PF-74. Subsequently, molecular dynamics simulation (MD) revealed potential interactions between representative compounds with HIV-1 CA hexamer. Overall, this work laid a solid foundation for further structural optimization to discover novel promising HIV-1 CA inhibitors.

To further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), a new series of diarylpyrimidines (DAPYs) were designed and synthesized as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs). The target compounds were evaluated for anti-HIV potency in MT-4 cells. Most of the synthesized DAPYs exhibited moderate to excellent activity against the HIV-1 wild-type (WT) strain with EC50 values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC50 values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC50(IIIB) = 16 nM, EC50(K103N) = 39 nM, SI = 294) was identified as the most significant compound, which was considerably more potent than nevirapine, lamivudine, and comparable to zidovudine. Additionally, the HIV-1 RT inhibition assay confirmed their binding target. Preliminary structure-activity relationships (SARs) and molecular modeling studies were also performed, providing significant suggestions for further optimization. ispartof: BIOORGANIC & MEDICINAL CHEMISTRY vol:42 ispartof: location:England status: published

Background aims Tissue engineering technology is a promising therapeutic strategy in peripheral nerve injury. Schwann cells (SCs) are deemed to be a vital component of cell-based nerve regeneration therapies. Many methods for producing SC-like cells derived from adipose-derived stromal cells (ADSCs) have been explored, but their phenotypic and functional characteristics remain unsatisfactory. Methods We investigated whether human ADSCs can be induced to differentiate into mature and stable SC-like cells with the addition of insulin, progestero``ne and glucocorticoids. The phenotypic and functional characteristics of new differentiated ADSCs (modified SC-like cells) were evaluated by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunocytochemistry in vitro. Cells loaded into collagen sponge biomaterials were implanted around transected sciatic nerves with a 10-mm gap in vivo. The axon regrowth and functional recovery of the regenerated nerves were assessed by immunohistochemistry and Walking footprint analysis. Results After differentiation induction, the modified SC-like cells showed significantly up-regulated levels of S100B and P0 and enhanced proliferative and migratory capacities. In addition, the modified SC-like cells showed increased secretion of neurotrophic factors, and their functional characteristics were maintained for more than 3 weeks after removing the induction reagents. The modified SC-like cells exhibited significantly enhanced axon regrowth, myelination and functional recovery after sciatic nerve injury. Conclusions Overall, the results suggest that this modified induction method can induce human ADSCs to differentiate into cells with the molecular and functional properties of mature SCs and increase the promotion of peripheral nerve regeneration.

A novel series of 3-hydroxyquinazoline-2,4(1H,3H)-diones derivatives has been designed and synthesized. Their biochemical characterization revealed that most of the compounds were effective inhibitors of HIV-1 RNase H activity at sub to low micromolar concentrations. Among them, II-4 was the most potent in enzymatic assays, showing an IC50 value of 0.41 ± 0.13 μM, almost five times lower than the IC50 obtained with β-thujaplicinol. In addition, II-4 was also effective in inhibiting HIV-1 IN strand transfer activity (IC50 = 0.85 ± 0.18 μM) but less potent than raltegravir (IC50 = 71 ± 14 nM). Despite its relatively low cytotoxicity, the efficiency of II-4 in cell culture was limited by its poor membrane permeability. Nevertheless, structure-activity relationships and molecular modeling studies confirmed the importance of tested 3-hydroxyquinazoline-2,4(1H,3H)-diones as useful leads for further optimization.

Introduction: Click chemistry has been exploited widely in the past to expedite lead discovery and optimization. Indeed, Copper-catalyzed azide-alkyne cycloaddition (CuAAC) click chemistry is a bioorthogonal reaction of widespread utility throughout medicinal chemistry and chemical biology. Areas covered: The authors review recent applications of CuAAC click chemistry to drug discovery based on the literature published since 2013. Furthermore, the authors provide the reader with their expert perspectives on the area including their outlook on future developments. Expert opinion: Click chemistry reactions are an important part of the medicinal chemistry toolbox and offer substantial advantages to medicinal chemists in terms of overcoming the limitations of useful chemical synthesis, increasing throughput, and improving the quality of compound libraries. To explore new chemical spaces for drug-like molecules containing a high degree of structural diversity, it may be useful to merge the diversity-oriented synthesis and 'privileged' substructure-based strategy with bioorthogonal reactions using sophisticated automation and flow systems to improve productivity. Large compound libraries obtained in this way should be of great value for the discovery of bioactive compounds and therapeutic agents.

CB2 (cannabinoid receptor 2) agonists have been shown to exert anti-tumor activities in different tumor types. However, there is no study exploring the role of MDA19 (a novel CB2 agonist) in tumors. In this study we aimed to investigate the effects of MDA19 treatment on HCC cell lines, Hep3B and HepG2 and determine the relevant mechanisms. Cell proliferation analysis, including CCK8 and colony formation assays, indicated that MDA19 treatment inhibited HCC cell proliferation in a dose- and time-dependent manner. Flow cytometry suggested that MDA19 induced cell apoptosis and activation of mitochondrial apoptosis pathway. Transwell assay indicated that HCC cell migration and invasion were significantly inhibited by MDA19 treatment. Mechanism investigation suggested that MDA19 induced inactivation of AKT signaling pathway in HCC cells. In addition, we investigated the function of CB2receptor in HCC and its role in the anti-tumor activity of MDA19. By searching on Kaplan-Meier plotter ( http://kmplot.com/analysis/ ), we found that HCC patients with high CB2 expression had a better survival and CB2 expression was significantly associated with gender, clinical stages and race of HCC patients (P

In this review, we provide an overview of recent applications of crystallographic overlay-based molecular structure hybridization of lead compounds as a rational strategy for efficient drug discovery, with selected examples, and briefly discuss its advantages compared with other ligand-based methodologies.

Two novel series of human immunodeficiency virus-1 (HIV-1) non-nucleoside reverse transcriptase inhibitors (NNRTIs) bearing a thiophene[3,2-d]pyrimidine scaffold and sulfonamide linker in the right wing have been identified, which demonstrated activity against the wild-type (WT) HIV-1 strain in MT-4 cells with inhibitory concentrations ranging from micromolar to submicromolar. Especially, against the mutant strains K103N and E138K, most compounds exhibited more potent activity than against WT HIV-1. Compound 7 (EC50 = 0.014, 0.031 μM) achieved the most potent activity against the two mutants, being more effective than that of nevirapine (NVP, EC50 = 7.572, 0.190 μM) and comparable to that of etravirine (ETV, EC50 = 0.004, 0.014 μM). Molecular docking experiments on the novel analogs have also suggested that the extensive network of main chain hydrogen bonds are important in the binding mode, which may provide valuable insights for further optimization.

A novel series of acetamide-substituted derivatives and two prodrugs of doravirine were designed and synthesized as potent HIV-1 NNRTIs by employing the structure-based drug design strategy. In MT-4 cell-based assays using the MTT method, it was found that most of the new compounds exhibited moderate to excellent inhibitory potency against the wild-type (WT) HIV-1 strain with a minimum EC50 value of 54.8 nM. Among them, the two most potent compounds 8i (EC50 = 59.5 nM) and 8k (EC50 = 54.8 nM) displayed robust activity against WT HIV-1 with double-digit nanomolar EC50 values, being superior to lamivudine (3TC, EC50 = 12.8 μM) and comparable to doravirine (EC50 = 13 nM). Besides, 8i and 8k shown moderate activity against the double RT mutant (K103N + Y181C) HIV-1 RES056 strain. The HIV-1 RT inhibition assay further validated the binding target. Molecular simulation of the representative compounds was employed to provide insight on their structure-activity relationships (SARs) and direct future design efforts. Finally, the aqueous solubility and chemical stability of the prodrugs 9 and 10 were investigated in detail.

To address drug resistance to HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs), a series of novel diarylpyrimidine (DAPY) derivatives targeting “tolerant region I” and “tolerant region II” of the NNRTIs binding pocket (NNIBP) were designed utilizing a structure-guided scaffold-hopping strategy. The dihydrofuro[3,4-d]pyrimidine derivatives 13c2 and 13c4 proved to be exceptionally potent against a wide range of HIV-1 strains carrying single NNRTI-resistant mutations (EC(50) = 0.9–8.4 nM), which were remarkably superior to that of etravirine (ETV). Meanwhile, both compounds exhibited comparable activities with ETV toward the virus with double mutations F227L+V106A and K103N+Y181C. Furthermore, the most active compound 13c2 showed favorable pharmacokinetic properties with an oral bioavailability of 30.96% and a half-life of 11.1 h, which suggested that 13c2 is worth further investigation as a novel NNRTI to circumvent drug resistance.

Enlightened by our previous efforts to modify diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) and the reported crystallographic studies, we designed and synthesized novel 1,2,3-triazole-derived diarylpyrimidine derivatives via the CuAAC “click reaction”, to make additional interactions with the hydrophobic channel in the NNRTI binding pocket. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells. All the compounds showed favorable activity against the wild-type HIV-1 strain with an EC50 of 0.013–5.62 μM. Interestingly, some compounds displayed remarkable potency in inhibiting K103N mutant virus, a key drug-resistant mutant to NNRTIs. Among them, meta-methylbenzoate (ZL2, EC50(IIIB) = 0.020 μM, EC50(K103N) = 0.043 μM, CC50 > 241.52 μM), para-methylbenzoate (ZL3, EC50(IIIB) = 0.013 μM, EC50 (K103N) = 0.022 μM, CC50 > 241.52 μM) and para-phenol (ZL7, EC50(IIIB) = 0.014 μM, EC50 (K103N) = 0.054 μM, CC50 = 2.1 μM) derivatives are the three most promising compounds which are superior to the first-line antiretroviral drug efavirenz (EC50(IIIB) = 0.003 μM, EC50 (K103N) = 0.11 μM, CC50 > 6.34 μM) against the K103N mutant strain. More encouragingly, ZL2 and ZL3 exhibited much lower cytotoxicity and a high selection index of >10 000 compared with all the control drugs (AZT, 3TC, NVP, EFV, and ETV). The detailed structure–activity relationship (SAR), enzymatic inhibitory activity and docking study of the representative compounds are also discussed. Furthermore, the preliminary physicochemical properties and the early metabolic stability of representative compounds were examined to evaluate their drug-like properties.

Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity, and low toxicity in antiretroviral combination therapies used to treat HIV. Until now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis, and clinical requirements for drugs.

GLS4, a potent antiviral drug candidate, has been widely studied and entered into phase II clinical trials. Nevertheless, the therapeutic application of GLS4 is limited due to poor water solubility, short half-life, and low bioavailability. In order to improve the hydrophilicity and pharmacokinetic (PK) properties of GLS4, herein, we retained the dominant fragments, and used a scaffold hopping strategy to replace the easily metabolized morpholine ring of GLS4 with diverse sizes of spiro rings consisting of hydrogen bond donor and acceptor substituents. Potent in vitro anti-HBV activity and low cytotoxicity were observed for compound 4r (EC50 = 0.20 ± 0.00 μM, CC50 > 87.03 μM), which was more potent than the positive control lamivudine (EC50 = 0.37 ± 0.04 μM, CC50 > 100.00 μM) in this assay and was about a quarter as effective as GLS4 (EC50 = 0.045 ± 0.01 μM, CC50 > 99.20 μM). Preliminary structure-activity relationship (SAR) analysis and molecular docking studies were carried out to explore potential interactions and binding mode between compounds and target protein. In terms of the physicochemical properties, 4r was predicted to be consistent with the rule-of-five, which means 4r may have favourable absorption and permeation. Finally, ADMET and PK characteristics of 4r and GLS4 were predicted to be comparable in most aspects, implying that the two compounds may have similar profiles in vivo.

Despite significant advances in antiretroviral therapy, acquired immunodeficiency syndrome remains as one of the leading causes of death worldwide. New antiretroviral drugs combined with updated treatment strategies are needed to improve convenience, tolerability, safety, and antiviral efficacy of available therapies. In this work, a focused library of coumarin derivatives was exploited by cell phenotypic screening to discover novel inhibitors of HIV-1 replication. Five compounds (DW-3, DW-4, DW-11, DW-25 and DW-31) showed moderate activity against wild-type and drug-resistant strains of HIV-1 (IIIB and RES056). Four of those molecules were identified as inhibitors of the viral RT-associated RNase H. Structural modification of the most potent DW-3 and DW-4 led to the discovery of compound 8a. This molecule showed increased potency against wild-type HIV-1 strain (EC = 3.94 ± 0.22 μM) and retained activity against a panel of mutant strains, showing EC values ranging from 5.62 μM to 202 μM. In enzymatic assays, 8a was found to inhibit the viral RNase H with an IC of 12.3 μM. Molecular docking studies revealed that 8a could adopt a binding mode similar to that previously reported for other active site HIV-1 RNase H inhibitors., Natural Science Foundation of China (NSFC Nos. 81973181, 81903453), Shandong Provincial Key research and development project (Nos. 2019JZZY021011), Shandong Provincial Natural Science Foundation (ZR2019BH011, ZR2020YQ61, ZR2020JQ31), Foreign cultural and educational experts Project (GXL20200015001), Qilu Young Scholars Program of Shandong University, the Taishan Scholar Program at Shandong Province, and KU Leuven (GOA 10/014). Work in Madrid was supported by the Spanish Ministry of Science and Innovation (grant PID2019-104176RB-I00/AEI/10.13039/501100011033), and an institutional grant of Fundación Ramón Areces (Madrid, Spain).

There is an urgent unmet medical need for novel human immunodeficiency virus type 1 (HIV-1) inhibitors that are effective against a variety of NNRTI-resistance mutations. We report our research efforts aimed at discovering a novel chemotype of anti-HIV-1 agents with improved potency against a variety of NNRTI-resistance mutations in this paper. Structural modifications of the lead K-5a2 led to the identification of a potent inhibitor 16c. 16c yielded highly potent anti-HIV-1 activities and improved resistance profiles compared with the approved drug etravirine. The co-crystal structure revealed the key role of the water networks surrounding the NNIBP for binding and for resilience against resistance mutations, while suggesting further extension of 16c toward the NNRTI-adjacent site as a lead development strategy. Furthermore, 16c demonstrated favorable pharmacokinetic and safety properties, suggesting the potential of 16c as a promising anti-HIV-1 drug candidate.

Recent coronavirus outbreaks of SARS-CoV-1 (2002–2003), MERS-CoV (since 2012), and SARS-CoV-2 (since the end of 2019) are examples of how viruses can damage health care and generate havoc all over the world. Coronavirus can spread quickly from person to person causing high morbidity and mortality. Unfortunately, the antiviral armamentarium is insufficient to fight these infections. In this chapter, we provide a detailed summary of the current situation in the development of drugs directed against pandemic human coronaviruses. Apart from the recently licensed remdesivir, other antiviral agents discussed in this review include molecules targeting viral components (e.g., RNA polymerase inhibitors, entry inhibitors, or protease inhibitors), compounds interfering with virus-host interactions, and drugs identified in large screening assays, effective against coronavirus replication, but with an uncertain mechanism of action., Financial support from the Key Project of NSFC for International Cooperation (No. 81420108027), and the Key Research and Development Project of Shandong Province (No. 2017CXGC1401, 2019JZZY021011, 2020SFXGFY08) are gratefully acknowledged. Work in Madrid was supported by grants of the Ministry of Science and Innovation of Spain (PID2019-104176RB-I00/AEI/10.13039/501100011033) and CSIC (2019AEP001). An institutional grant of the Fundación Ramón Areces to the CBMSO is also acknowledged.

Abstract: COVID-19 is an infectious disease caused by SARS-CoV-2. The life cycle of SARS-CoV-2 includes the entry into the target cells, replicase translation, replicating and transcribing genomes, translating structural proteins, assembling and releasing new virions. Entering host cells is a crucial stage in the early life cycle of the virus, and blocking this stage can effectively prevent virus infection. SARS enters the target cells mediated by the interaction between the viral S protein and the target cell surface receptor angiotensin- converting enzyme 2 (ACE2), as well as the cleavage effect of a type-II transmembrane serine protease (TMPRSS2) on the S protein. Therefore, the ACE2 receptor and TMPRSS2 are important targets for SARS-CoV-2 entry inhibitors. Herein, we provide a concise report/information on drugs with potential therapeutic value targeting virus-ACE2 or virus-TMPRSS2 interactions to provide a reference for the design and discovery of potential entry inhibitors against SARS-CoV-2.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has quickly spread worldwide and has affected more than 10 million individuals. A typical feature of COVID-19 is the suppression of type I and III interferon (IFN)-mediated antiviral immunity. However, the molecular mechanism by which SARS-CoV-2 evades antiviral immunity remains elusive. Here, we reported that the SARS-CoV-2 membrane (M) protein inhibits the production of type I and III IFNs induced by the cytosolic dsRNA-sensing pathway mediated by RIG-I/MDA-5–MAVS signaling. In addition, the SARS-CoV-2 M protein suppresses type I and III IFN induction stimulated by SeV infection or poly (I:C) transfection. Mechanistically, the SARS-CoV-2 M protein interacts with RIG-I, MAVS, and TBK1, thus preventing the formation of the multiprotein complex containing RIG-I, MAVS, TRAF3, and TBK1 and subsequently impeding the phosphorylation, nuclear translocation, and activation of IRF3. Consequently, ectopic expression of the SARS-CoV-2 M protein facilitates the replication of vesicular stomatitis virus. Taken together, these results indicate that the SARS-CoV-2 M protein antagonizes type I and III IFN production by targeting RIG-I/MDA-5 signaling, which subsequently attenuates antiviral immunity and enhances viral replication. This study provides insight into the interpretation of SARS-CoV-2-induced antiviral immune suppression and illuminates the pathogenic mechanism of COVID-19.