Accelerating antiviral drug discovery: lessons from COVID-19

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(7), P. 585 - 603

Published: May 12, 2023

Language: Английский

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Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance

EBioMedicine, Journal Year: 2023, Volume and Issue: 91, P. 104559 - 104559

Published: April 14, 2023

Nirmatrelvir-ritonavir (Paxlovid) and ensitrelvir are 3-chymotrypsin-like cysteine protease (3CLpro) inhibitors which have been approved for the treatment of COVID-19 in 2021 2022, respectively. Previous studies identified 3CLpro mutations that associated with reduced susceptibility to these antivirals. The aim current study was estimate global prevalence inhibitor-resistant SARS-CoV-2 strains.We compiled a list nirmatrelvir or resistance based on either viral replication activity assays, determined their among 13.4 million sequences deposited GISAID as December 14, about 1 year after approval nirmatrelvir-ritonavir. We analyzed different time periods, lineages geographical locations.Overall, 0.5% (67,095/13,446,588) contained at least one mutation shown affect inhibitory activity. did not observe any increasing trend widespread clinical use G15S (2070 per million) T21I (1386 were most prevalent mutations, dominant some lineages. E166V S144E, previously by > 100-folds, found <1 sequences.Our data suggest inhibitor is currently rare. However, continuous genotypic phenotypic surveillance would be crucial early detection resistant mutants.Richard Carol Yu, May Tam Mak Mei Yin, Shaw Foundation Hong Kong, Michael Tong, Marina Lee, Government Consultancy Service, Emergency Key Program Guangzhou Laboratory (See acknowledgements full list).

Language: Английский

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Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19

JAMA Network Open, Journal Year: 2024, Volume and Issue: 7(2), P. e2354991 - e2354991

Published: Feb. 9, 2024

Importance Treatment options for COVID-19 are warranted irrespective of the presence risk factors severe disease. Objective To assess efficacy and safety ensitrelvir in patients with mild to moderate COVID-19. Design, Setting, Participants This phase 3 part a 2/3, double-blind, placebo-controlled randomized clinical trial was conducted from February 10 July 10, 2022, 28-day follow-up period, at 92 institutions Japan, Vietnam, South Korea. Patients (aged 12 &amp;lt;70 years) within 120 hours positive viral test results were studied. Interventions (1:1:1) receive 125 mg once-daily (375 on day 1), 250 (750 or placebo 5 days. Main Outcomes Measures The primary end point time resolution composite characteristic symptoms SARS-CoV-2 Omicron infection, assessed using Peto-Prentice generalized Wilcoxon stratified by vaccination history. Virologic also assessed. Results A total 1821 randomized, whom 1030 (347 125-mg group, 340 250-mg 343 group) less than 72 disease onset (primary analysis population). mean (SD) age this population 35.2 (12.3) years, 552 (53.6%) men. significant difference observed between group ( P = .04 test). median approximately 1 (167.9 vs 192.2 hours; difference, −24.3 95% CI, −78.7 11.7 hours). Adverse events 267 604 (44.2%) 321 599 150 605 (24.8%) which included decrease high-density lipoprotein level (188 [31.1%] 231 [38.6%] 23 [3.8%] group). No treatment-related serious adverse reported. Conclusions Relevance In trial, treatment reduced typical compared treated onset; absolute day. Ensitrelvir demonstrated antiviral without new concerns. Generalizability populations outside Asia should be confirmed. Trial Registration Japan Registry Clinical Trials Identifier: jRCT2031210350

Language: Английский

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Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2

Med, Journal Year: 2023, Volume and Issue: 4(11), P. 813 - 824.e4

Published: Sept. 7, 2023

Antiviral and antibody therapies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being recommended high-risk patients, but the potential development of multidrug-resistant mutations in immunocompromised patients is unclear.To investigate treatment course cases prolonged viral shedding an patient with SARS-CoV-2 infection, we conducted longitudinal measurements laboratory tests, chest computed tomography (CT) image evaluations, titers, antigen levels nasopharyngeal swabs. Furthermore, performed whole-genome sequencing digital PCR analysis to examine mechanisms drug resistance.We present a case 65-year-old man history malignant lymphoma who was treated multiple antiviral therapies, including sotrovimab, remdesivir, paxlovid (nirmatrelvir/ritonavir), molnupiravir. Initially, decreased after treatments. However, virus rebounded, showed no virologic response. The genome revealed single Omicron subvariant (BA.1.1), which evolved within host during disease progression. viruses had acquired resistance nirmatrelvir (3 chymotrypsin-like protease [3CLpro] E166 A/V), sotrovimab (spike P337L E340K), remdesivir (RNA-dependent RNA polymerase [RdRp] V166L).Our results indicate that survival fitness persist infected subpopulation selection pressure.This study supported by JSPS KAKENHI Early-Career Scientists 18K16292 (Y.H.), Grant-in-Aid Scientific Research (B) 20H03668 23H02955 YASUDA Medical Foundation Uehara Memorial Takeda Science Kato Bioscience (Y.H.).

Language: Английский

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Fluorine-a small magic bullet atom in the drug development: perspective to FDA approved and COVID-19 recommended drugs

Chemical Papers, Journal Year: 2023, Volume and Issue: 77(8), P. 4085 - 4106

Published: April 13, 2023

Language: Английский

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In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: July 15, 2023

Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against including its omicron variants. Since most subvariants have reduced sensitivity to monoclonal antibody therapies, resistance other antivirals inhibitors such as ensitrelvir major public health concern. Here, repeating passages of in the presence revealed M49L and E166A substitutions Nsp5 are responsible for ensitrelvir. Both vitro virus growth absence The combination allowed largely evade suppressive effect vitro. possessing Nsp5-M49L showed similar pathogenicity wild-type virus, whereas Nsp5-E166A Nsp5-M49L/E166A slightly attenuated. Ensitrelvir treatment hamsters infected with was ineffective; however, nirmatrelvir molnupiravir effective. Therefore, it important closely monitor emergence ensitrelvir-resistant variants guide selection.

Language: Английский

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A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part)

Medicine, Journal Year: 2023, Volume and Issue: 102(8), P. e33024 - e33024

Published: Feb. 22, 2023

Limited treatment options exist for patients with mild-to-moderate coronavirus disease 2019 (COVID-19), irrespective of vaccination history or risk status. Ensitrelvir is a novel oral severe acute respiratory syndrome 2 (SARS-CoV-2) 3C-like (3CL) protease inhibitor. While phase studies ensitrelvir have demonstrated promising results in treating COVID-19, evaluation its clinical efficacy due to shifting status and emergence the Omicron variant represents significant challenges. Here, we describe protocol 3 study designed evaluate safety regardless history.This multicenter, randomized, double-blind, placebo-controlled, study. Patients COVID-19 within 120 hours from onset will be randomized 1:1:1 ratio into arms-ensitrelvir 125 mg (375 loading dose on Day 1), 250 (750 placebo. The interventions administered orally, once-daily, 5 days. primary endpoint time resolution symptoms (stuffy runny nose, sore throat, cough, feeling hot feverish, low energy tiredness), key secondary endpoints include change baseline 4 amount SARS-CoV-2 viral ribonucleic acid (RNA) first negative titer. population <72 randomization and, subsequently, entire patient (<120 hours) group. Closed testing procedure used both populations. All assessments adverse events (AE) reported.In post hoc analysis 2b study, compared placebo, reduced COVID-19. Through this intend validate establish

Language: Английский

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Antitarget, Anti-SARS-CoV-2 Leads, Drugs, and the Drug Discovery–Genetics Alliance Perspective

Journal of Medicinal Chemistry, Journal Year: 2023, Volume and Issue: 66(6), P. 3664 - 3702

Published: March 1, 2023

The most advanced antiviral molecules addressing major SARS-CoV-2 targets (Main protease, Spike protein, and RNA polymerase), compared with proteins of other human pathogenic coronaviruses, may have a short-lasting clinical efficacy. Accumulating knowledge on the mechanisms underlying target structural basis, its mutational progression, related biological significance to virus replication allows envisaging development better-targeted therapies in context COVID-19 epidemic future coronavirus outbreaks. identification evolutionary patterns based solely sequence information analysis for those can provide meaningful insights into molecular basis host–pathogen interactions adaptation, leading drug resistance phenomena. Herein, we will explore how study observed predicted mutations offer valuable suggestions application so-called “synthetic lethal” strategy Main protease protein. synergy between genetics evidence discovery prioritize novel long-lasting agents.

Language: Английский

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SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

Future Pharmacology, Journal Year: 2023, Volume and Issue: 3(1), P. 80 - 107

Published: Jan. 9, 2023

While the COVID-19 pandemic seems to be on its decline, unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not underestimated threat. These along with preparedness, ask for an alert identification new drugs optimization existing as therapeutic treatment options this potential future diseases. Mpro inhibitors were identified early potent drug candidates against coronaviruses, since they target viable processing machinery within virus, i.e., main protease that cleaves polyproteins encoded by viral RNA into functional proteins. Different strategies, including reversible irreversible inhibition well allosteric inhibitors, mostly from repurposing endeavors, have been explored design SARS-CoV-2 antivirals. Ambitious screening efforts uttered outstanding chemical structural diversity, which has led half dozen lead compounds being currently clinical trials emergency FDA approval ritonavir-boosted nirmatrelvir therapeutic. This comprehensive analysis achieved inhibitor diversity sorted irreversible, reversible, binders, discussion emerging resistance reports possible evasion is aimed at stimulating continuing efforts.

Language: Английский

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SARS-CoV-2 resistance to monoclonal antibodies and small-molecule drugs

Cell chemical biology, Journal Year: 2024, Volume and Issue: 31(4), P. 632 - 657

Published: April 1, 2024

Over four years have passed since the beginning of COVID-19 pandemic. The scientific response has been rapid and effective, with many therapeutic monoclonal antibodies small molecules developed for clinical use. However, given ability viruses to become resistant antivirals, it is perhaps no surprise that field identified resistance nearly all these compounds. Here, we provide a comprehensive review profile each therapeutics. We hope this resource provides an atlas mutations be aware agent, particularly as springboard considerations next generation antivirals. Finally, discuss outlook thoughts moving forward in how continue manage this, next,

Language: Английский

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