Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir
作者全名："Duan, Yinkai; Zhou, Hao; Liu, Xiang; Iketani, Sho; Lin, Mengmeng; Zhang, Xiaoyu; Bian, Qucheng; Wang, Haofeng; Sun, Haoran; Hong, Seo Jung; Culbertson, Bruce; Mohri, Hiroshi; Luck, Maria I.; Zhu, Yan; Liu, Xiaoce; Lu, Yuchi; Yang, Xiuna; Yang, Kailin; Sabo, Yosef; Chavez, Alejandro; Goff, Stephen P.; Rao, Zihe; Ho, David D.; Yang, Haitao"
作者地址："[Duan, Yinkai; Zhou, Hao; Lin, Mengmeng; Zhang, Xiaoyu; Bian, Qucheng; Wang, Haofeng; Sun, Haoran; Zhu, Yan; Liu, Xiaoce; Lu, Yuchi; Yang, Xiuna; Rao, Zihe; Yang, Haitao] ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China; [Duan, Yinkai; Zhou, Hao; Lin, Mengmeng; Zhang, Xiaoyu; Bian, Qucheng; Wang, Haofeng; Sun, Haoran; Zhu, Yan; Liu, Xiaoce; Lu, Yuchi; Yang, Xiuna; Rao, Zihe; Yang, Haitao] ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China; [Duan, Yinkai; Zhou, Hao; Zhang, Xiaoyu; Bian, Qucheng; Wang, Haofeng; Sun, Haoran; Zhu, Yan; Liu, Xiaoce; Lu, Yuchi; Yang, Xiuna; Yang, Haitao] Shanghai Clin Res & Trial Ctr, Shanghai, Peoples R China; [Liu, Xiang] Nankai Univ, Coll Life Sci, State Key Lab Med Chem Biol, Tianjin, Peoples R China; [Iketani, Sho; Mohri, Hiroshi; Luck, Maria I.; Sabo, Yosef; Goff, Stephen P.; Ho, David D.] Columbia Univ, Vagelos Coll Phys & Surg, Aaron Diamond AIDS Res Ctr, New York, NY 10027 USA; [Iketani, Sho; Mohri, Hiroshi; Luck, Maria I.; Sabo, Yosef; Ho, David D.] Columbia Univ, Vagelos Coll Phys & Surg, Dept Med, Div Infect Dis, New York, NY 10027 USA; [Lin, Mengmeng] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Zhang, Xiaoyu; Lu, Yuchi] Lingang Lab, Shanghai, Peoples R China; [Hong, Seo Jung; Chavez, Alejandro] Columbia Univ, Vagelos Coll Phys & Surg, Dept Pathol & Cell Biol, New York, NY USA; [Culbertson, Bruce] Columbia Univ, Vagelos Coll Phys & Surg, Integrated Program Cellular Mol & Biomed Studies, New York, NY USA; [Culbertson, Bruce] Columbia Univ, Vagelos Coll Phys & Surg, Med Scientist Training Program, New York, NY USA; [Culbertson, Bruce; Chavez, Alejandro] Univ Calif San Diego, Dept Pediat, La Jolla, CA USA; [Yang, Kailin] Cleveland Clin, Taussig Canc Ctr, Cleveland, OH USA; [Goff, Stephen P.; Ho, David D.] Columbia Univ, Vagelos Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10027 USA; [Goff, Stephen P.] Columbia Univ, Vagelos Coll Phys & Surg, Dept Biochem & Mol Biophys, New York, NY USA; [Rao, Zihe] Tsinghua Univ, Sch Med, MOE Key Lab Prot Sci, Beijing, Peoples R China; [Rao, Zihe] Innovat Ctr Pathogen Res, Guangzhou Lab, Guangzhou, Peoples R China; [Rao, Zihe] Nankai Univ, Coll Life Sci, State Key Lab Med Chem Biol, Tianjin, Peoples R China; [Rao, Zihe] Nankai Univ, Coll Pharm, Tianjin, Peoples R China; [Rao, Zihe] Chinese Acad Sci, Inst Biophys, CAS Ctr Excellence Biomacromol, Natl Lab Biomacromol, Beijing, Peoples R China"
通信作者："Yang, HT (通讯作者)，ShanghaiTech Univ, Shanghai Inst Adv Immunochem Studies, Shanghai, Peoples R China.; Yang, HT (通讯作者)，ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China.; Yang, HT (通讯作者)，Shanghai Clin Res & Trial Ctr, Shanghai, Peoples R China.; Ho, DD (通讯作者)，Columbia Univ, Vagelos Coll Phys & Surg, Aaron Diamond AIDS Res Ctr, New York, NY 10027 USA.; Ho, DD (通讯作者)，Columbia Univ, Vagelos Coll Phys & Surg, Dept Med, Div Infect Dis, New York, NY 10027 USA.; Ho, DD (通讯作者)，Columbia Univ, Vagelos Coll Phys & Surg, Dept Microbiol & Immunol, New York, NY 10027 USA."
来源：NATURE
ESI学科分类：Multidisciplinary
WOS号：WOS:001075493300001
JCR分区：Q1
影响因子：50.5
年份：2023
卷号：
期号：
开始页：
结束页：
文献类型：Article; Early Access
关键词：
摘要："Nirmatrelvir is a specific antiviral drug that targets the main protease (Mpro) of SARS-CoV-2 and has been approved to treat COVID-191,2. As an RNA virus characterized by high mutation rates, whether SARS-CoV-2 will develop resistance to nirmatrelvir is a question of concern. Our previous studies have shown that several mutational pathways confer resistance to nirmatrelvir, but some result in a loss of viral replicative fitness, which is then compensated for by additional alterations3. The molecular mechanisms for this observed resistance are unknown. Here we combined biochemical and structural methods to demonstrate that alterations at the substrate-binding pocket of Mpro can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of the structures of 14 Mpro mutants in complex with drugs or substrate revealed that alterations at the S1 and S4 subsites substantially decreased the level of inhibitor binding, whereas alterations at the S2 and S4 ' subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, with the latter compensating for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness, as observed previously3. Such a profile was also observed for ensitrelvir, another clinically relevant Mpro inhibitor. These results shed light on the mechanisms by which SARS-CoV-2 evolves to develop resistance to the current generation of protease inhibitors and provide the basis for the design of next-generation Mpro inhibitors. A biochemical and structural analysis demonstrates that alterations at the substrate-binding pocket of the main protease of SARS-CoV-2 can allow the virus to develop resistance to nirmatrelvir in two distinct ways."
基金机构："We acknowledge the Discovery Technology Platform of the Shanghai Institute for Advanced Immunochemical Studies and the Molecular and Cell Biology Core Facility of the School of Life Science and Technology, ShanghaiTech University for use of their instrumen; Discovery Technology Platform of the Shanghai Institute for Advanced Immunochemical Studies; ShanghaiTech University [SRPG22-003, SRPG22-011]; Guangzhou Laboratory [YDZX20213100001556, 20XD1422900]; Science and Technology Commission of Shanghai Municipality [92169109]; National Natural Science Foundation of China; Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine of ShanghaiTech University; Career Award for Medical Scientists from the Burroughs Wellcome Fund"
基金资助正文："We acknowledge the Discovery Technology Platform of the Shanghai Institute for Advanced Immunochemical Studies and the Molecular and Cell Biology Core Facility of the School of Life Science and Technology, ShanghaiTech University for use of their instrumentation and technical assistance; and the staff members from beamlines BL02U1, BL10U2, BL18U1 and BL19U1 at the Shanghai Synchrotron Radiation Facility and the I04 beamline of the Diamond Light Source for the beam time and operation at the facility. This work was supported by grants from Guangzhou Laboratory (grant numbers SRPG22-003 and SRPG22-011); the Science and Technology Commission of Shanghai Municipality (grant numbers YDZX20213100001556 and 20XD1422900 to H.Y.); the National Natural Science Foundation of China (grant number 92169109 to H.Y.); and the Shanghai Frontiers Science Center for Biomacromolecules and Precision Medicine of ShanghaiTech University. A.C. is supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund."
