tetano
Editor, Senior Moderator
Sci Adv
. 2024 Jul 26;10(30):eadl4013.
doi: 10.1126/sciadv.adl4013. Epub 2024 Jul 24. In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance
Yuao Zhu[SUP] 1 [/SUP], Irina Yurgelonis[SUP] 1 [/SUP], Stephen Noell[SUP] 2 [/SUP], Qingyi Yang[SUP] 3 [/SUP], Shunjie Guan[SUP] 3 [/SUP], Zhenghui Li[SUP] 1 [/SUP], Li Hao[SUP] 1 [/SUP], Hussin Rothan[SUP] 1 [/SUP], Devendra K Rai[SUP] 1 [/SUP], Patricia McMonagle[SUP] 1 [/SUP], Mary Lynn Baniecki[SUP] 3 [/SUP], Samantha E Greasley[SUP] 4 [/SUP], Olga Plotnikova[SUP] 2 [/SUP], Jonathan Lee[SUP] 1 [/SUP], Jennifer A Nicki[SUP] 2 [/SUP], RoseAnn Ferre[SUP] 4 [/SUP], Laura J Byrnes[SUP] 2 [/SUP], Wei Liu[SUP] 4 [/SUP], Timothy K Craig[SUP] 2 [/SUP], Claire M Steppan[SUP] 2 [/SUP], Paul Liberator[SUP] 1 [/SUP], Holly D Soares[SUP] 2 [/SUP], Charlotte M N Allerton[SUP] 3 [/SUP], Annaliesa S Anderson[SUP] 1 [/SUP], Rhonda D Cardin[SUP] 1 [/SUP]
Affiliations
To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus M[SUP]pro[/SUP] inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six M[SUP]pro[/SUP] mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and M[SUP]pro[/SUP] activity. SARS-CoV-2 surveillance revealed that in vitro resistance-associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19-related hospitalization or death.
. 2024 Jul 26;10(30):eadl4013.
doi: 10.1126/sciadv.adl4013. Epub 2024 Jul 24. In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance
Yuao Zhu[SUP] 1 [/SUP], Irina Yurgelonis[SUP] 1 [/SUP], Stephen Noell[SUP] 2 [/SUP], Qingyi Yang[SUP] 3 [/SUP], Shunjie Guan[SUP] 3 [/SUP], Zhenghui Li[SUP] 1 [/SUP], Li Hao[SUP] 1 [/SUP], Hussin Rothan[SUP] 1 [/SUP], Devendra K Rai[SUP] 1 [/SUP], Patricia McMonagle[SUP] 1 [/SUP], Mary Lynn Baniecki[SUP] 3 [/SUP], Samantha E Greasley[SUP] 4 [/SUP], Olga Plotnikova[SUP] 2 [/SUP], Jonathan Lee[SUP] 1 [/SUP], Jennifer A Nicki[SUP] 2 [/SUP], RoseAnn Ferre[SUP] 4 [/SUP], Laura J Byrnes[SUP] 2 [/SUP], Wei Liu[SUP] 4 [/SUP], Timothy K Craig[SUP] 2 [/SUP], Claire M Steppan[SUP] 2 [/SUP], Paul Liberator[SUP] 1 [/SUP], Holly D Soares[SUP] 2 [/SUP], Charlotte M N Allerton[SUP] 3 [/SUP], Annaliesa S Anderson[SUP] 1 [/SUP], Rhonda D Cardin[SUP] 1 [/SUP]
Affiliations
- PMID: 39047088
- PMCID: PMC11268423
- DOI: 10.1126/sciadv.adl4013
To facilitate the detection and management of potential clinical antiviral resistance, in vitro selection of drug-resistant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) against the virus M[SUP]pro[/SUP] inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six M[SUP]pro[/SUP] mutation patterns containing T304I alone or in combination with T21I, L50F, T135I, S144A, or A173V emerged, with A173V+T304I and T21I+S144A+T304I mutations showing >20-fold resistance each. Biochemical analyses indicated inhibition constant shifts aligned to antiviral results, with S144A and A173V each markedly reducing nirmatrelvir inhibition and M[SUP]pro[/SUP] activity. SARS-CoV-2 surveillance revealed that in vitro resistance-associated mutations from our studies and those reported in the literature were rarely detected in the Global Initiative on Sharing All Influenza Data database. In the Paxlovid Evaluation of Protease Inhibition for COVID-19 in High-Risk Patients trial, E166V was the only emergent resistance mutation, observed in three Paxlovid-treated patients, none of whom experienced COVID-19-related hospitalization or death.