Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system

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Abstract

The oral protease inhibitor nirmatrelvir is of key importance for prevention of severe coronavirus disease 2019 (COVID-19). To facilitate resistance monitoring, we studied severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) escape from nirmatrelvir in cell culture. Resistant variants harbored combinations of substitutions in the SARS-CoV-2 main protease (Mpro). Reverse genetics revealed that E166V and L50F + E166V conferred high resistance in infectious culture, replicon, and Mpro systems. While L50F, E166V, and L50F + E166V decreased replication and Mpro activity, L50F and L50F + E166V variants had high fitness in the infectious system. Naturally occurring L50F compensated for fitness cost of E166V and promoted viral escape. Molecular dynamics simulations revealed that E166V and L50F + E166V weakened nirmatrelvir-Mpro binding. Polymerase inhibitor remdesivir and monoclonal antibody bebtelovimab retained activity against nirmatrelvir-resistant variants, and combination with nirmatrelvir enhanced treatment efficacy compared to individual compounds. These findings have implications for monitoring and ensuring treatments with efficacy against SARS-CoV-2 and emerging sarbecoviruses.

Abstract

Specific SARS-CoV-2 main protease substitutions mediate high nirmatrelvir resistance and fitness in an infectious culture system.

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Most cited references 52

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GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers

Mark Abraham, Teemu Murtola, Roland Schulz … (2015)

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Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

Victor M Corman, Olfert Landt, Marco Kaiser … (2020)

Background The ongoing outbreak of the recently emerged novel coronavirus (2019-nCoV) poses a challenge for public health laboratories as virus isolates are unavailable while there is growing evidence that the outbreak is more widespread than initially thought, and international spread through travellers does already occur. Aim We aimed to develop and deploy robust diagnostic methodology for use in public health laboratory settings without having virus material available. Methods Here we present a validated diagnostic workflow for 2019-nCoV, its design relying on close genetic relatedness of 2019-nCoV with SARS coronavirus, making use of synthetic nucleic acid technology. Results The workflow reliably detects 2019-nCoV, and further discriminates 2019-nCoV from SARS-CoV. Through coordination between academic and public laboratories, we confirmed assay exclusivity based on 297 original clinical specimens containing a full spectrum of human respiratory viruses. Control material is made available through European Virus Archive – Global (EVAg), a European Union infrastructure project. Conclusion The present study demonstrates the enormous response capacity achieved through coordination of academic and public laboratories in national and European research networks.

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Remdesivir for the Treatment of Covid-19 — Final Report

John H. Beigel, Kay Tomashek, Lori Dodd … (2022)

Abstract Background Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious. Methods We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only. Results A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%). Conclusions Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACTT-1 ClinicalTrials.gov number, NCT04280705.)

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Contributors

Yuyong Zhou:

ORCID: https://orcid.org/0000-0001-6330-3170

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - review & editing

Karen Anbro Gammeltoft:

ORCID: https://orcid.org/0000-0003-0469-767X

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Line Abildgaard Ryberg:

ORCID: https://orcid.org/0000-0002-5301-0232

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Long V. Pham: Role: Investigation

Helena Damtoft Tjørnelund:

ORCID: https://orcid.org/0000-0001-8648-3266

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Visualization

Alekxander Binderup:

ORCID: https://orcid.org/0000-0001-7344-433X

Role: InvestigationRole: Validation

Carlos Rene Duarte Hernandez: Role: InvestigationRole: Writing - review & editing

Carlota Fernandez-Antunez: Role: Investigation

Anna Offersgaard:

ORCID: https://orcid.org/0000-0002-7748-2840

Role: InvestigationRole: Writing - review & editing

Ulrik Fahnøe:

ORCID: https://orcid.org/0000-0002-2527-5751

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: SoftwareRole: VisualizationRole: Writing - review & editing

Günther Herbert Johannes Peters:

ORCID: https://orcid.org/0000-0001-9754-2663

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: SoftwareRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Santseharay Ramirez:

ORCID: https://orcid.org/0000-0003-3699-1814

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - review & editing

Jens Bukh:

ORCID: https://orcid.org/0000-0002-7815-4806

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: Writing - review & editing

Judith Margarete Gottwein:

ORCID: https://orcid.org/0000-0003-2805-0256

Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: December 2022

Publication date (Electronic, pub): 21 December 2022

Volume: 8

Issue: 51

Electronic Location Identifier: eadd7197

Affiliations

[ ¹ ]Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases, Copenhagen University Hospital–Hvidovre, 2650 Hvidovre, Denmark.

[ ² ]CO-HEP, Department of Immunology and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark.

[ ³ ]Department of Chemistry, Technical University of Denmark, 2800 Kongens Lyngby, Denmark.

Author notes

[* ]Corresponding author. Email: jgottwein@ 123456sund.ku.dk

[†]

These authors contributed equally to this work.

Author information

Yuyong Zhou https://orcid.org/0000-0001-6330-3170

Karen Anbro Gammeltoft https://orcid.org/0000-0003-0469-767X

Line Abildgaard Ryberg https://orcid.org/0000-0002-5301-0232

Helena Damtoft Tjørnelund https://orcid.org/0000-0001-8648-3266

Alekxander Binderup https://orcid.org/0000-0001-7344-433X

Anna Offersgaard https://orcid.org/0000-0002-7748-2840

Ulrik Fahnøe https://orcid.org/0000-0002-2527-5751

Günther Herbert Johannes Peters https://orcid.org/0000-0001-9754-2663

Santseharay Ramirez https://orcid.org/0000-0003-3699-1814

Jens Bukh https://orcid.org/0000-0002-7815-4806

Judith Margarete Gottwein https://orcid.org/0000-0003-2805-0256

Article

Publisher ID: add7197

DOI: 10.1126/sciadv.add7197

PMC ID: 9770952

PubMed ID: 36542720

SO-VID: 65c8f24f-7db8-434a-83ec-406f3573080f

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).

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This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 29 June 2022

Date accepted : 17 November 2022

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100009584, Toyota Foundation;

Funded by: FundRef http://dx.doi.org/10.13039/501100004543, China Scholarship Council;

Funded by: FundRef http://dx.doi.org/10.13039/501100011747, Novo Nordisk Foundation Center for Basic Metabolic Research;

Funded by: FundRef http://dx.doi.org/10.13039/501100013826, Candys Foundation;

Funded by: Innovation Fund Denmark;

Funded by: Danish Agency for Science and Higher Education;

Funded by: Weimann Foundation;

Funded by: Amager and Hvidovre Hospital Research Foundation;

Funded by: Region H Foundation;

Funded by: Independent Research Fund Denmark;

Funded by: Mauritzen la Fontaine Foundation;

Funded by: Region H Foundation;

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Nirmatrelvir-resistant SARS-CoV-2 variants with high fitness in an infectious cell culture system

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Novel Coronavirus Disease COVID-19

Most cited references 52

GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers

Detection of 2019 novel coronavirus (2019-nCoV) by real-time RT-PCR

Remdesivir for the Treatment of Covid-19 — Final Report

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Cited by 47

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