Multiple pathways for SARS-CoV-2 resistance to nirmatrelvir

Nature, Год журнала: 2022, Номер 613(7944), С. 558 - 564

Опубликована: Ноя. 9, 2022

Nirmatrelvir, an oral antiviral targeting the 3CL protease of SARS-CoV-2, has been demonstrated to be clinically useful against COVID-19 (refs. 1,2). However, because SARS-CoV-2 evolved become resistant other therapeutic modalities3-9, there is a concern that same could occur for nirmatrelvir. Here we examined this possibility by in vitro passaging nirmatrelvir using two independent approaches, including one on large scale. Indeed, highly viruses emerged from both and their sequences showed multitude mutations. In experiment peformed with many replicates, 53 viral lineages were selected mutations observed at 23 different residues enzyme. Nevertheless, several common mutational pathways resistance preferred, majority descending T21I, P252L or T304I as precursor Construction analysis 13 recombinant clones these mediated only low-level resistance, whereas greater required accumulation additional E166V mutation conferred strongest (around 100-fold), but resulted loss replicative fitness was restored compensatory changes such L50F T21I. Our findings indicate does readily arise via multiple vitro, specific herein form strong foundation which study mechanism detail inform design next-generation inhibitors.

Язык: Английский

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The Substitutions L50F, E166A, and L167F in SARS-CoV-2 3CLpro Are Selected by a Protease Inhibitor In Vitro and Confer Resistance To Nirmatrelvir

mBio, Год журнала: 2023, Номер 14(1)

Опубликована: Янв. 10, 2023

The SARS-CoV-2 main protease (3CLpro) has an indispensable role in the viral life cycle and is a therapeutic target for treatment of COVID-19. potential 3CLpro-inhibitors to select drug-resistant variants needs be established. Therefore, was passaged vitro presence increasing concentrations ALG-097161, probe compound designed context 3CLpro drug discovery program. We identified combination amino acid substitutions (L50F E166A L167F) that associated with >20× increase 50% effective concentration (EC50) values nirmatrelvir (PF-07321332), PF-00835231, ensitrelvir. While two single (E166A provide low-level resistance inhibitors biochemical assay, triple mutant results highest levels (6× 72×). All are significant loss enzymatic activity, suggesting reduction fitness. Structural biology analysis indicates different reduce number inhibitor/enzyme interactions while binding substrate maintained. These observations will important interpretation development clinical setting. IMPORTANCE Paxlovid first oral antiviral approved infection. Antiviral treatments often viruses. In order guide use novel antivirals, it essential understand risk characterize changes genes proteins. this work, we describe time pathway allows develop against vitro. characteristics may predictive situation. our work management COVID-19 next-generation inhibitors.

Язык: Английский

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Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study

Clinical Infectious Diseases, Год журнала: 2022, Номер 76(8), С. 1403 - 1411

Опубликована: Дек. 7, 2022

This phase 2b part of a randomized 2/3 study assessed the efficacy and safety ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during Omicron epidemic.Patients were (1:1:1) to orally receive fumaric acid 125 mg (375 on day 1) or 250 (750 placebo once daily 5 days. The co-primary endpoints change from baseline in severe acute respiratory syndrome 2 (SARS-CoV-2) titer 4 time-weighted average up 120 hours total score predefined 12 COVID-19 symptoms. Safety was through adverse events.A 341 patients (ensitrelvir 125-mg group: 114; 250-mg 116; 111; male: 53.5-64.9%; mean age: 35.3-37.3 years) included analyses. SARS-CoV-2 significantly greater with both doses than (differences placebo: -0.41 log10 50% tissue-culture infectious dose/mL; P < .0001 both). symptoms did not show significant difference between groups group. versus several subtotal scores, including Most events mild severity.Ensitrelvir treatment demonstrated favorable antiviral potential clinical benefit an acceptable profile.Japan Registry Clinical Trials: jRCT2031210350 (https://jrct.niph.go.jp/en-latest-detail/jRCT2031210350).

Язык: Английский

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SARS-CoV-2 3CL ^pro mutations selected in a VSV-based system confer resistance to nirmatrelvir, ensitrelvir, and GC376

Science Translational Medicine, Год журнала: 2022, Номер 15(678)

Опубликована: Окт. 4, 2022

Protease inhibitors are among the most powerful antiviral drugs. Nirmatrelvir is first protease inhibitor specifically developed against SARS-CoV-2 3CLpro that has been licensed for clinical use. To identify mutations confer resistance to this inhibitor, we engineered a chimeric vesicular stomatitis virus (VSV) expressed polyprotein composed of VSV glycoprotein (G), 3CLpro, and polymerase (L). Viral replication was thus dependent on autocatalytic processing precursor protein by release functional viral proteins G L, effectively inhibited nirmatrelvir. Using system, applied nirmatrelvir select mutations. Resistance confirmed retesting selected in additional VSV-based systems, an independently cellular biochemical assay, recombinant system. We demonstrate some mutants cross-resistant ensitrelvir GC376, whereas others less resistant these compounds. Furthermore, found already existed sequences have deposited NCBI GISAID databases, indicating were present circulating strains.

Язык: Английский

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Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir

Nature, Год журнала: 2023, Номер 622(7982), С. 376 - 382

Опубликована: Сен. 11, 2023

Язык: Английский

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Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors

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

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S-217622, a SARS-CoV-2 main protease inhibitor, decreases viral load and ameliorates COVID-19 severity in hamsters

Science Translational Medicine, Год журнала: 2022, Номер 15(679)

Опубликована: Ноя. 3, 2022

In parallel with vaccination, oral antiviral agents are highly anticipated to act as countermeasures for the treatment of coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome 2 (SARS-CoV-2). Oral medication demands not only high activity but also target specificity, favorable bioavailability, and metabolic stability. Although a large number compounds have been identified potential inhibitors SARS-CoV-2 infection in vitro, few proven be effective vivo. Here, we show that administration S-217622 (ensitrelvir), an inhibitor main protease (Mpro; known 3C-like protease), decreases viral load ameliorates severity SARS-CoV-2-infected hamsters. inhibited proliferation at low nanomolar submicromolar concentrations cells. demonstrated pharmacokinetic properties accelerated recovery from hamster recipients. Moreover, exerted against variants concern, including pathogenic Delta variant recently emerged Omicron BA.5 BA.2.75 variants. Overall, our study provides evidence S-217622, agent is under evaluation phase 3 clinical trial (clinical registration no. jRCT2031210350), has remarkable potency efficacy prospective therapeutic option COVID-19.

Язык: Английский

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Insights for COVID-19 in 2023

Revista Española de Quimioterapia, Год журнала: 2022, Номер 36(2), С. 114 - 124

Опубликована: Дек. 12, 2022

Predictions for a near end of the pandemic by World Health Organization should be interpreted with caution. Current evidence indicates that efficacy fourth dose classical mRNA vaccines (BT162b2 or mRNA-1273) is low and short-lived in preventing SARS-CoV-2 infection its predominant variant (Omicron). However, high against severe symptomatic infection, hospitalization death. The new being introduced are bivalent active Omicron variants. Potential to coming year include vaccine based on recombinant protein emulates receptor binding domain Spike under development Spanish company Hipra, as well nasal oral administration. Available information suggests COVID-19 can administered association influenza vaccination without particular complications. New drugs COVID-19, both antiviral anti-inflammatory, investigation, but this does not seem case monoclonal antibodies. indication use masks some circumstances will maintained next view accumulation scientific data their efficacy. Finally, long COVID Post-COVID syndrome may continue affect very proportion patients who have had disease, requiring combined diagnostic therapeutic resources.

Язык: Английский

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Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19

New England Journal of Medicine, Год журнала: 2024, Номер 390(3), С. 230 - 241

Опубликована: Янв. 17, 2024

BackgroundSimnotrelvir is an oral 3-chymotrypsin–like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy a phase 1B trial.MethodsIn this 2–3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate disease 2019 (Covid-19) onset of symptoms within the past 3 days 1:1 ratio receive 750 mg simnotrelvir plus 100 ritonavir or placebo twice daily for 5 days. The primary end point was time sustained resolution symptoms, defined as absence 11 Covid-19–related consecutive Safety changes viral load were also assessed.ResultsA total 1208 enrolled at 35 sites China; 603 605 placebo. Among modified intention-to-treat population received first dose trial drug 72 hours after symptom onset, Covid-19 significantly shorter group than (180.1 [95% confidence interval {CI}, 162.1 201.6] vs. 216.0 CI, 203.4 228.1]; median difference, −35.8 −60.1 −12.4]; P=0.006 by Peto–Prentice test). On day 5, decrease from baseline greater (mean difference [±SE], −1.51±0.14 log10 copies per milliliter; 95% −1.79 −1.24). incidence adverse events during treatment higher (29.0% 21.6%). Most mild moderate.ConclusionsEarly administration shortened among adult with Covid-19, without evident safety concerns. (Funded Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.)

Язык: Английский

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

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

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