Global prevalence of SARS-CoV-2 3CL protease mutations associated with nirmatrelvir or ensitrelvir resistance

被引:54
|
作者
Ip, Jonathan Daniel [1 ]
Chu, Allen Wing-Ho [1 ]
Chan, Wan-Mui [1 ]
Leung, Rhoda Cheuk-Ying [1 ]
Abdullah, Syed Muhammad Umer [2 ]
Sun, Yanni [2 ]
To, Kelvin Kai -Wang [1 ,3 ,4 ,5 ]
机构
[1] Univ Hong Kong, Li Ka Shing Fac Med, Carol Yu Ctr Infect, State Key Lab Emerging Infect Dis,Dept Microbiol,S, Hong Kong, Peoples R China
[2] City Univ Hong Kong, Dept Elect Engn, Kowloon, Tat Chee Ave, Hong Kong, Peoples R China
[3] Queen Mary Hosp, Dept Microbiol, Pokfulam, 19th Floor,Block T, Hong Kong, Peoples R China
[4] Univ Hong Kong, Shenzhen Hosp, Dept Clin Microbiol & Infect Control, Shenzhen, Peoples R China
[5] Ctr Virol Vaccinol & Therapeut, Hong Kong Sci & Technol Pk, Hong Kong, Peoples R China
来源
EBIOMEDICINE | 2023年 / 91卷
关键词
COVID-19; SARS-CoV-2; Antiviral resistance; Nirmatrelvir; Ensitrelvir; Protease inhibitor;
D O I
10.1016/j.ebiom.2023.104559
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background 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 and 2022, respectively. Previous studies have identified 3CLpro mutations that are associated with reduced susceptibility to these antivirals. The aim of the current study was to estimate the global prevalence of 3CLpro inhibitor-resistant SARS-CoV-2 strains.Methods We compiled a list of 3CLpro mutations which have been associated with nirmatrelvir or ensitrelvir resis-tance based on either viral replication or 3CLpro activity assays, and determined their prevalence among 13.4 million sequences deposited in GISAID as of December 14, 2022, about 1 year after the approval of nirmatrelvir-ritonavir. We analyzed the prevalence for different time periods, SARS-CoV-2 lineages and geographical locations.Findings Overall, 0.5% (67,095/13,446,588) of the sequences contained at least one mutation that was shown to affect the inhibitory activity of nirmatrelvir or ensitrelvir on viral replication or 3CLpro activity. We did not observe any increasing trend of resistance after the widespread clinical use of nirmatrelvir-ritonavir. G15S (2070 per million) and T21I (1386 per million) were the most prevalent mutations, and these mutations were dominant in some SARS-CoV-2 lineages. E166V and S144E, previously shown to affect the inhibitory activity of nirmatrelvir on viral replication or protease activity by > 100-folds, were found in <1 per million sequences. Interpretation Our data suggest that 3CLpro inhibitor resistance is currently rare. However, continuous global genotypic and phenotypic surveillance would be crucial in the early detection of resistant mutants. Copyright (c) 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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页数:6
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