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1.
Tetrahedron Lett ; 104: 154012, 2022 Aug 17.
Article in English | MEDLINE | ID: covidwho-1984119

ABSTRACT

The COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is continuing to spread around the world. GS-441524 is the parent nucleoside of remdesivir which is the first drug approved for the treatment of COVID-19, and demonstrates strong activity against SARS-Cov-2 in vitro and in vivo. Herein, we reported the synthesis of a series of deuterated GS-441524 analogs, which had deuterium atoms up to five at the ribose and the nucleobase moieties. Compared to GS-441524, all the deuterated compounds showed similar inhibitory activities against SARS-CoV-2 in vitro.

2.
EuropePMC; 2020.
Preprint in English | EuropePMC | ID: ppcovidwho-323613

ABSTRACT

Objectives: COVID-19 remains a global challenge. Corticosteroids are a group of anti-inflammatory and suppressive immune response drugs that are widely used in the treatment of COVID-19, especially when it presents with viral pneumonia. Comprehensive reviews investigating the comparative proportion and efficacy of corticosteroid use are scarce. Therefore, we conducted a systematic review and meta-analysis of clinical trials to evaluate the proportion and efficacy of corticosteroid use for the treatment of COVID-19. Methods: : We conducted a comprehensive literature review of PubMed, EMBASE, the Cochrane Controlled Trials Registry, and the China Academic Journal Network Publishing Database for relevant trials on glucocorticoid therapy in COVID-19 patients. Outcome measures were the proportion of patients administered corticosteroids, viral clearance and mortality. Effect size was reported as weighted mean differences (WMDs) for continuous outcomes and odds ratios (ORs) for dichotomous outcomes with associated 95% confidence intervals (CIs). Results: : Forty-three trials involving 6603 patients were included. The meta-analysis demonstrated that the proportion of COVID-19 patients who received corticosteroids was significantly lower than that of patients who did not receive corticosteroids. In addition, our meta-analysis demonstrated no significant difference in the proportions of severe and nonsevere patients who were administered corticosteroids. We also performed subgroup analyses stratified by severity, indicating that the proportion of patients administered corticosteroids was significantly higher among intensive care unit (ICU) patients than among non-ICU patients. The results of our meta-analysis indicated that corticosteroid treatment significantly delayed the viral clearance time. Finally, our meta-analysis demonstrated no significant difference between the use of corticosteroids for COVID-19 patients who died and those who survived. This result indicated that mortality was not correlated with corticosteroid therapy. Conclusion: The proportion of COVID-19 patients who received corticosteroids was significantly lower than that of patients who did not receive corticosteroids. Corticosteroid use in subjects with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections delayed virus clearance and did not convincingly improve survival;therefore, corticosteroids should be used with caution in the treatment of COVID-19.

3.
J Nat Prod ; 85(2): 327-336, 2022 02 25.
Article in English | MEDLINE | ID: covidwho-1655431

ABSTRACT

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to more than 5 million deaths worldwide to date. Due to the limited therapeutic options so far available, target-based virtual screening with LC/MS support was applied to identify the novel and high-content compounds 1-4 with inhibitory effects on SARS-CoV-2 in Vero E6 cells from the plant Dryopteris wallichiana. These compounds were also evaluated against SARS-CoV-2 in Calu-3 cells and showed unambiguous inhibitory activity. The inhibition assay of targets showed that compounds 3 and 4 mainly inhibited SARS-CoV-2 3CLpro, with effective Kd values. Through docking and molecular dynamics modeling, the binding site is described, providing a comprehensive understanding of 3CLpro and interactions for 3, including hydrogen bonds, hydrophobic bonds, and the spatial occupation of the B ring. Compounds 3 and 4 represent new, potential lead compounds for the development of anti-SARS-CoV-2 drugs. This study has led to the development of a target-based virtual screening method for exploring the potency of natural products and for identifying natural bioactive compounds for possible COVID-19 treatment.


Subject(s)
Antiviral Agents/pharmacology , Biological Products/pharmacology , Microbial Sensitivity Tests/methods , Phloroglucinol/pharmacology , SARS-CoV-2/drug effects , Terpenes/pharmacology , Chromatography, High Pressure Liquid , Chromatography, Liquid , Crystallography, X-Ray , Drug Delivery Systems , Dryopteris/chemistry , Magnetic Resonance Spectroscopy , Mass Spectrometry , Molecular Docking Simulation , Molecular Structure , Virtual Reality
5.
Bioorg Med Chem ; 46: 116364, 2021 09 15.
Article in English | MEDLINE | ID: covidwho-1406212

ABSTRACT

The nucleoside metabolite of remdesivir, GS-441524 displays potent anti-SARS-CoV-2 efficacy, and is being evaluated in clinical as an oral antiviral therapeutic for COVID-19. However, this nucleoside has a poor oral bioavailability in non-human primates, which may affect its therapeutic efficacy. Herein, we reported a variety of GS-441524 analogs with modifications on the base or the sugar moiety, as well as some prodrug forms, including five isobutyryl esters, two l-valine esters, and one carbamate. Among the new nucleosides, only the 7-fluoro analog 3c had moderate anti-SARS-CoV-2 activity, and its phosphoramidate prodrug 7 exhibited reduced activity in Vero E6 cells. As for the prodrugs, the 3'-isobutyryl ester 5a, the 5'-isobutyryl ester 5c, and the tri-isobutyryl ester 5g hydrobromide showed excellent oral bioavailabilities (F = 71.6%, 86.6% and 98.7%, respectively) in mice, which provided good insight into the pharmacokinetic optimization of GS-441524.


Subject(s)
Adenosine/analogs & derivatives , Antiviral Agents/pharmacology , SARS-CoV-2/drug effects , Adenosine/pharmacokinetics , Adenosine/pharmacology , Adenosine/toxicity , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/pharmacokinetics , Antiviral Agents/toxicity , Chlorocebus aethiops , Male , Mice, Inbred ICR , Microbial Sensitivity Tests , Prodrugs/chemical synthesis , Prodrugs/pharmacokinetics , Prodrugs/pharmacology , Prodrugs/toxicity , Vero Cells
6.
J Med Chem ; 65(4): 2827-2835, 2022 02 24.
Article in English | MEDLINE | ID: covidwho-1366783

ABSTRACT

The receptor recognition of the novel coronavirus SARS-CoV-2 relies on the "down-to-up" conformational change in the receptor-binding domain (RBD) of the spike (S) protein. Therefore, understanding the process of this change at the molecular level facilitates the design of therapeutic agents. With the help of coarse-grained molecular dynamic simulations, we provide evidence showing that the conformational dynamics of the S protein are globally cooperative. Importantly, an allosteric path was discovered that correlates the motion of the RBD with the motion of the junction between the subdomain 1 (SD1) and the subdomain 2 (SD2) of the S protein. Building on this finding, we designed non-RBD binding modulators to inhibit SARS-CoV-2 by prohibiting the conformational change of the S protein. Their inhibition effect and function stages at inhibiting SARS-CoV-2 were evaluated experimentally. In summary, our studies establish a molecular basis for future therapeutic agent design through allosteric effects.


Subject(s)
Antiviral Agents/pharmacology , Molecular Dynamics Simulation , SARS-CoV-2/drug effects , Small Molecule Libraries/pharmacology , Spike Glycoprotein, Coronavirus/antagonists & inhibitors , Allosteric Regulation/drug effects , Animals , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Cells, Cultured , Chlorocebus aethiops , Drug Evaluation, Preclinical , Humans , Microbial Sensitivity Tests , Molecular Structure , SARS-CoV-2/metabolism , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Spike Glycoprotein, Coronavirus/metabolism , Vero Cells
7.
Nat Commun ; 12(1): 3623, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1270656

ABSTRACT

The ongoing pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) urgently needs an effective cure. 3CL protease (3CLpro) is a highly conserved cysteine proteinase that is indispensable for coronavirus replication, providing an attractive target for developing broad-spectrum antiviral drugs. Here we describe the discovery of myricetin, a flavonoid found in many food sources, as a non-peptidomimetic and covalent inhibitor of the SARS-CoV-2 3CLpro. Crystal structures of the protease bound with myricetin and its derivatives unexpectedly revealed that the pyrogallol group worked as an electrophile to covalently modify the catalytic cysteine. Kinetic and selectivity characterization together with theoretical calculations comprehensively illustrated the covalent binding mechanism of myricetin with the protease and demonstrated that the pyrogallol can serve as an electrophile warhead. Structure-based optimization of myricetin led to the discovery of derivatives with good antiviral activity and the potential of oral administration. These results provide detailed mechanistic insights into the covalent mode of action by pyrogallol-containing natural products and a template for design of non-peptidomimetic covalent inhibitors against 3CLpros, highlighting the potential of pyrogallol as an alternative warhead in design of targeted covalent ligands.


Subject(s)
Coronavirus 3C Proteases/drug effects , Pyrogallol/chemistry , Pyrogallol/isolation & purification , Pyrogallol/pharmacology , SARS-CoV-2/drug effects , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , COVID-19/drug therapy , Coronavirus Papain-Like Proteases , Drug Design , Flavonoids , HEK293 Cells , Humans , Kinetics , Ligands , Molecular Dynamics Simulation , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacology , Viral Nonstructural Proteins/chemistry
8.
PLoS One ; 16(4): e0249481, 2021.
Article in English | MEDLINE | ID: covidwho-1197372

ABSTRACT

OBJECTIVES: Coronavirus disease 2019 (COVID-19) remains a global challenge. Corticosteroids constitute a group of anti-inflammatory and immunosuppressive drugs that are widely used in the treatment of COVID-19. Comprehensive reviews investigating the comparative proportion and efficacy of corticosteroid use are scarce. Therefore, we conducted a systematic review and meta-analysis of clinical trials to evaluate the proportion and efficacy of corticosteroid use for the treatment of COVID-19. METHODS: We conducted a comprehensive literature review and meta-analysis of research articles, including observational studies and clinical trials, by searching the PubMed, EMBASE, Cochrane Controlled Trials Registry, and China Academic Journal Network Publishing databases. Patients treated between December 1, 2019, and January 1, 2021, were included. The outcome measures were the proportion of patients treated with corticosteroids, viral clearance and mortality. The effect size with the associated 95% confidence interval is reported as the weighted mean difference for continuous outcomes and the odds ratio for dichotomous outcomes. RESULTS: Fifty-two trials involving 15710 patients were included. The meta-analysis demonstrated that the proportion of COVID-19 patients who received corticosteroids was significantly lower than that of patients who did not receive corticosteroids (35.19% vs. 64.49%). In addition, our meta-analysis demonstrated no significant difference in the proportions of severe and nonsevere cases treated with corticosteroids (27.91% vs. 20.91%). We also performed subgroup analyses stratified by whether patients stayed in the intensive care unit (ICU) and found that the proportion of patients who received corticosteroids was significantly higher among those who stayed in the ICU than among those who did not. The results of our meta-analysis indicate that corticosteroid treatment significantly delayed the viral clearance time. Finally, our meta-analysis demonstrated no significant difference in the use of corticosteroids for COVID-19 between patients who died and those who survived. This result indicates that mortality is not correlated with corticosteroid therapy. CONCLUSION: The proportion of COVID-19 patients who received corticosteroids was significantly lower than that of patients who did not receive corticosteroids. Corticosteroid use in subjects with severe acute respiratory syndrome coronavirus 2 infections delayed viral clearance and did not convincingly improve survival; therefore, corticosteroids should be used with extreme caution in the treatment of COVID-19.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/drug therapy , Anti-Inflammatory Agents/therapeutic use , COVID-19/virology , Humans , Intensive Care Units , Randomized Controlled Trials as Topic , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Treatment Outcome
9.
Eur J Clin Microbiol Infect Dis ; 40(2): 373-379, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1033857

ABSTRACT

Quorum sensing (QS) inhibition is an essential strategy to combat bacterial infection. Previously, we have synthesized a series of thymidine derivatives bearing isoxazole and 1,2,3-triazole rings (TITL). Herein, the inhibitory effects of TITL on QS of Pseudomonas aeruginosa PAO1 were evaluated. In vitro results demonstrated that TITL effectively inhibited biofilm formation and reduced the virulence factors of P. aeruginosa PAO1. In combination with antibiotics, our TITL compounds significantly prolonged the lifespans of Caenorhabditis elegans N2 nematodes that were infected with P. aeruginosa PAO1 in vivo. In conclusion, TITL compounds are promising candidates for the treatment of antibiotic-resistant P. aeruginosa PAO1.


Subject(s)
Biofilms/drug effects , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/drug effects , Quorum Sensing/drug effects , Triazoles/pharmacology , Virulence/drug effects , Animals , Anti-Bacterial Agents/pharmacology , Caenorhabditis elegans , Drug Resistance, Bacterial
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