In vitro selection and analysis of SARS-CoV-2 nirmatrelvir resistance mutations contributing to clinical virus resistance surveillance.

Autor:	Zhu Y; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Yurgelonis I; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Noell S; Pfizer Worldwide Research, Development & Medical, Groton, CT 06340, USA., Yang Q; Pfizer Worldwide Research, Development & Medical, Cambridge MA 02139, USA., Guan S; Pfizer Worldwide Research, Development & Medical, Cambridge MA 02139, USA., Li Z; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Hao L; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Rothan H; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Rai DK; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., McMonagle P; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Baniecki ML; Pfizer Worldwide Research, Development & Medical, Cambridge MA 02139, USA., Greasley SE; Pfizer Worldwide Research, Development & Medical, La Jolla, CA 92121, USA., Plotnikova O; Pfizer Worldwide Research, Development & Medical, Groton, CT 06340, USA., Lee J; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Nicki JA; Pfizer Worldwide Research, Development & Medical, Groton, CT 06340, USA., Ferre R; Pfizer Worldwide Research, Development & Medical, La Jolla, CA 92121, USA., Byrnes LJ; Pfizer Worldwide Research, Development & Medical, Groton, CT 06340, USA., Liu W; Pfizer Worldwide Research, Development & Medical, La Jolla, CA 92121, USA., Craig TK; Pfizer Worldwide Research, Development & Medical, Groton, CT 06340, USA., Steppan CM; Pfizer Worldwide Research, Development & Medical, Groton, CT 06340, USA., Liberator P; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Soares HD; Pfizer Worldwide Research, Development & Medical, Groton, CT 06340, USA., Allerton CMN; Pfizer Worldwide Research, Development & Medical, Cambridge MA 02139, USA., Anderson AS; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA., Cardin RD; Pfizer Worldwide Research, Development & Medical, Pearl River, NY 10965, USA.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2024 Jul 26; Vol. 10 (30), pp. eadl4013. Date of Electronic Publication: 2024 Jul 24.
DOI:	10.1126/sciadv.adl4013
Abstrakt:	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 pro inhibitor nirmatrelvir (Paxlovid active component) was conducted. Six M pro 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 pro 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.
Databáze:	MEDLINE
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