Chen Pu, Van Oers Tayla J, Arutyunova Elena, Fischer Conrad, Wang Chaoxiang, Lamer Tess, van Belkum Marco J, Young Howard S, Vederas John C, Lemieux M Joanne
Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
JACS Au. 2024 Jul 30;4(8):3217-3227. doi: 10.1021/jacsau.4c00508. eCollection 2024 Aug 26.
Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (M) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of M hinders the processing of the proteins essential for viral replication . However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 M at 2.0 Å resolution. In addition, we show that ibuzatrelvir also potently inhibits the M of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV M. In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with M of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals.
伊布扎特雷韦尔（1）最近由辉瑞公司披露并获得专利，用于治疗严重急性呼吸综合征冠状病毒2（SARS-CoV-2）。它已获得美国食品药品监督管理局（FDA）的快速通道地位，并已进入III期临床试验，可能成为帕罗韦德的替代品。与帕罗韦德中的奈玛特韦（2）一样，这种口服活性候选药物旨在通过其腈弹头与类胰凝乳蛋白酶样半胱氨酸蛋白酶（3CL蛋白酶）活性位点硫醇的可逆共价相互作用来靶向病毒主要蛋白酶（M）。抑制M会阻碍病毒复制所必需的蛋白质的加工。然而，伊布扎特雷韦尔显然不需要利托那韦（3），帕罗韦德中联合使用利托那韦是为了阻断奈玛特韦的人体氧化代谢。在此，我们报告了伊布扎特雷韦尔与SARS-CoV-2 M活性位点复合物的晶体结构，分辨率为2.0 Å。此外，我们表明伊布扎特雷韦尔也能有效抑制中东呼吸综合征相关冠状病毒（MERS-CoV）的M，幸运的是，MERS-CoV并不广泛传播，但可能具有致命危险（死亡率约为36%）。共晶体结构表明，该药物与两个活性位点的结合模式相似，抑制剂的三氟甲基精确地契合到主要蛋白酶的关键S2底物结合口袋中。然而，我们的结果也为伊布扎特雷韦尔对这两种蛋白酶效力差异提供了一个解释，这是由于底物偏好的微小差异导致MERS-CoV M中的氢键网络较弱。此外，我们研究了化合物与两种蛋白酶结合的可逆性，这是减少脱靶效应以及潜在免疫原性的一个重要参数。伊布扎特雷韦尔与SARS-CoV-2和MERS-CoV的M形成的复合物的晶体结构将进一步有助于人类和动物冠状病毒感染的药物设计。
