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上海科技大学杨海涛等研究人员合作揭示SARS-CoV-2对nirmatrelvir抗药性的分子机制。该项研究成果于2023年9月11日在线发表在《自然》杂志上。

研究人员表示，nirmatrelvir是一种针对SARS-CoV-2主要蛋白酶（M^pro）的特异性抗病毒药物，已被批准用于治疗COVID-19。作为一种以高突变率为特征的RNA病毒，SARS-CoV-2是否会对nirmatrelvir产生耐药性是一个令人担忧的问题。研究人员以前的发现表明，有几种突变途径会产生对nirmatrelvir的耐药性，但其中一些途径会导致病毒复制能力的丧失，而这又会被其他突变所弥补。这种耐药性的分子机制尚不清楚。

研究人员结合生化和结构方法证明了M^pro底物结合袋的突变可使SARS-CoV-2以两种不同的方式对nirmatrelvir产生耐药性。对14个M^pro突变体与药物或底物的复合结构进行的综合研究显示，S1和S4亚位点的突变显著降低了抑制剂的结合力，而S2和S4'亚位点的突变则意外地提高了蛋白酶的活性。这两种机制都对nirmatrelvir产生了抗性，而后者弥补了前者酶活性的损失，这反过来又是之前观察到的病毒复制能力恢复的原因。在另一种临床相关的M^pro抑制剂ensitrelvir中也观察到了这种情况。

这些研究结果揭示了SARS-CoV-2演变为对现有蛋白酶抑制剂产生抗药性的机制，并为设计下一代M^pro抑制剂提供了依据。

附：英文原文

Title: Molecular mechanisms of SARS-CoV-2 resistance to nirmatrelvir

Author: 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

Issue&Volume: 2023-09-11

Abstract: Nirmatrelvir is a specific antiviral targeting 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 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 in turn are compensated by additional mutations3. The molecular mechanisms for this observed resistance are yet unknown. Here we combined biochemical and structural methods to demonstrate that mutations at the substrate binding pocket of the Mpro can allow SARS-CoV-2 to develop resistance to nirmatrelvir in two distinct ways. Comprehensive studies of 14 complex structures of Mpro mutants with drugs or substrate revealed that mutations at the S1 and S4 subsites significantly decreased inhibitor binding, while mutations at the S2 and S4’ subsites unexpectedly increased protease activity. Both mechanisms contributed to nirmatrelvir resistance, whereas the latter compensated for the loss in enzymatic activity of the former, which in turn accounted for the restoration of viral replicative fitness as we have 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.

DOI: 10.1038/s41586-023-06609-0

Source: https://www.nature.com/articles/s41586-023-06609-0

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