Study of key residues in MERS-CoV and SARS-CoV-2 main proteases for resistance against clinically applied inhibitors nirmatrelvir and ensitrelvir DOI Creative Commons
Laura Krismer, Helge Schöppe, Stefanie Rauch

и другие.

npj Viruses, Год журнала: 2024, Номер 2(1)

Опубликована: Июнь 24, 2024

Abstract The Middle East Respiratory Syndrome Coronavirus (MERS-CoV) is an epidemic, zoonotically emerging pathogen initially reported in Saudi Arabia 2012. MERS-CoV has the potential to mutate or recombine with other coronaviruses, thus acquiring ability efficiently spread among humans and become pandemic. Its high mortality rate of up 35% absence effective targeted therapies call for development antiviral drugs this pathogen. Since beginning SARS-CoV-2 pandemic, extensive research focused on identifying protease inhibitors treatment SARS-CoV-2. Our intention was therefore assess whether these are viable options combating MERS-CoV. To that end, we used previously established assays quantify inhibition SARS-CoV-2, main proteases. Nirmatrelvir inhibited several proteases, whereas ensitrelvir less broadly active. simulate nirmatrelvir’s clinical use against subsequent resistance development, applied a safe, surrogate virus-based system. Using virus, selected hallmark mutations SARS-CoV-2-M pro , such as T21I, M49L, S144A, E166A/K/V L167F. In current study, pool MERS-CoV-M mutants, characterized modelled steric effect catalytic site mutants S142G, S142R, S147Y A171S.

Язык: Английский

Therapeutic strategies for COVID-19: progress and lessons learned DOI Open Access
Guangdi Li, Rolf Hilgenfeld, Richard J. Whitley

и другие.

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 22(6), С. 449 - 475

Опубликована: Апрель 19, 2023

Язык: Английский

Процитировано

405
A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-Like Protease Inhibitor, in Japanese Patients with Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part DOI Creative Commons
Hiroshi Mukae, Hiroshi Yotsuyanagi, Norio Ohmagari

и другие.

Antimicrobial Agents and Chemotherapy, Год журнала: 2022, Номер 66(10)

Опубликована: Сен. 13, 2022

This multicenter, double-blind, phase 2a part of a 2/3 study assessed the efficacy and safety ensitrelvir, novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like protease inhibitor, in Japanese patients with mild-to-moderate disease 2019 (COVID-19) or asymptomatic SARS-CoV-2 infection. Sixty-nine were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 daily, 750 250 daily) placebo up until 28.

Язык: Английский

Процитировано

101
Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors DOI Creative Commons
Melissa L. Boby, D. Fearon, Matteo P. Ferla

и другие.

Science, Год журнала: 2023, Номер 382(6671)

Опубликована: Ноя. 9, 2023

We report the results of COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. discovered noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, high-throughput structural biology chemistry. generated detailed map plasticity SARS-CoV-2 protease, extensive structure-activity relationships for multiple chemotypes, wealth biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay (>10,000 measurements), synthesized molecules (>2400 compounds) this were shared rapidly openly, creating rich, open, intellectual property–free knowledge base future anticoronavirus discovery.

Язык: Английский

Процитировано

88
Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance DOI Creative Commons
Jonathan Daniel Ip,

Allen Wing‐Ho Chu,

Wan-Mui Chan

и другие.

EBioMedicine, Год журнала: 2023, Номер 91, С. 104559 - 104559

Опубликована: Апрель 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).

Язык: Английский

Процитировано

72
Antiviral efficacy of molnupiravir versus ritonavir-boosted nirmatrelvir in patients with early symptomatic COVID-19 (PLATCOV): an open-label, phase 2, randomised, controlled, adaptive trial DOI Creative Commons
William HK Schilling, Podjanee Jittamala, James A Watson

и другие.

The Lancet Infectious Diseases, Год журнала: 2023, Номер 24(1), С. 36 - 45

Опубликована: Сен. 28, 2023

Molnupiravir and ritonavir-boosted nirmatrelvir are the two leading oral COVID-19 antiviral treatments, but their activities in patients have not been compared directly. The aim of this ongoing platform trial is to compare different treatments using rate viral clearance as measure effect.

Язык: Английский

Процитировано

57
Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19 DOI Creative Commons
Hiroshi Yotsuyanagi, Norio Ohmagari, Yohei Doi

и другие.

JAMA Network Open, Год журнала: 2024, Номер 7(2), С. e2354991 - e2354991

Опубликована: Фев. 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

Язык: Английский

Процитировано

55
Design of a SARS-CoV-2 papain-like protease inhibitor with antiviral efficacy in a mouse model DOI Open Access
Bin Tan, Xiaoming Zhang, Ahmadullah Ansari

и другие.

Science, Год журнала: 2024, Номер 383(6690), С. 1434 - 1440

Опубликована: Март 28, 2024

The emergence of SARS-CoV-2 variants and drug-resistant mutants calls for additional oral antivirals. papain-like protease (PL pro ) is a promising but challenging drug target. We designed synthesized 85 noncovalent PL inhibitors that bind to recently discovered ubiquitin binding site the known BL2 groove pocket near S4 subsite. Leads inhibited with inhibitory constant K i values from 13.2 88.2 nanomolar. co-crystal structures eight leads revealed their interaction modes. in vivo lead Jun12682 its variants, including nirmatrelvir-resistant strains EC 50 0.44 2.02 micromolar. Oral treatment improved survival reduced lung viral loads lesions infection mouse model, suggesting are antiviral candidates.

Язык: Английский

Процитировано

47
A Second-Generation Oral SARS-CoV-2 Main Protease Inhibitor Clinical Candidate for the Treatment of COVID-19 DOI Creative Commons
Charlotte Allerton,

Joel T. Arcari,

Lisa Aschenbrenner

и другие.

Journal of Medicinal Chemistry, Год журнала: 2024, Номер 67(16), С. 13550 - 13571

Опубликована: Апрель 30, 2024

Despite the record-breaking discovery, development and approval of vaccines antiviral therapeutics such as Paxlovid, coronavirus disease 2019 (COVID-19) remained fourth leading cause death in world third highest United States 2022. Here, we report discovery characterization PF-07817883, a second-generation, orally bioavailable, SARS-CoV-2 main protease inhibitor with improved metabolic stability versus nirmatrelvir, component ritonavir-boosted therapy Paxlovid. We demonstrate

Язык: Английский

Процитировано

23
A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part) DOI Creative Commons
Hiroshi Yotsuyanagi, Norio Ohmagari, Yohei Doi

и другие.

Medicine, Год журнала: 2023, Номер 102(8), С. e33024 - e33024

Опубликована: Фев. 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

Язык: Английский

Процитировано

39
In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir DOI Creative Commons
Maki Kiso, Seiya Yamayoshi, Shun Iida

и другие.

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Июль 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.

Язык: Английский

Процитировано

39