尼马替韦尔是帕克洛维德的主要成分，这是一个口服抗病毒药物，用于治疗由SARS-COV-2感染引起的COVID-19。尼马替韦尔靶向主要蛋白酶（Mpro），在不同冠状病毒中保持了较高的一致性。我们的分子对接分析表明，尼马替韦尔与SARS-CoV-2和三种季节性冠状病毒（OC43，229E和NL63）的Mpro酶的亲和力相当。然而，在细胞培养模型中，我们发现尼马替韦尔强烈抑制了SARS-CoV-2、OC43和229E，但对NL63没有影响。在病毒复制和感染滴度水平上均表明，NL63对尼马替韦尔的治疗不敏感。我们进一步在人类气道器官样本中证实了尼马替韦尔对OC43和229E的抗病毒活性。尼马替韦尔和莫卢匹韦组合在抗OC43和229E冠状病毒方面的反应模式有所差异。这些结果揭示了尼马替韦尔抑制不同冠状病毒的能力存在差异，并提醒不要将其作为泛冠状病毒治疗的重新用途。版权所有©2023作者。由Elsevier B.V.出版，版权所有。

Nirmatrelvir is the main component of Paxlovid, an oral antiviral drug approved for the treatment of COVID-19 caused by SARS-COV-2 infection. Nirmatrelvir targets the main protease (Mpro), which is substantially conserved among different coronaviruses. Here, our molecular docking analysis indicates comparable affinity of nirmatrelvir binding to the Mpro enzymes of SARS-CoV-2 and three seasonal coronaviruses (OC43, 229E and NL63). However, in cell culture models, we found that nirmatrelvir potently inhibited SARS-CoV-2, OC43 and 229E, but not NL63. The insensitivity of NL63 to nirmatrelvir treatment was demonstrated at both viral replication and infectious titer levels. The antiviral activity of nirmatrelvir against OC43 and 229E was further confirmed in human airway organoids. The combination of nirmatrelvir and molnupiravir exerted differential patterns of antiviral response against OC43 and 229E. These results revealed disparities in the ability of nirmatrelvir to inhibit different coronaviruses, and caution against repurposing of nirmatrelvir as a pan-coronavirus treatment.Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.