College of Pharmaceutical Sciences, Gannan Medical Universitygrid.440714.2, Ganzhou, China.
School of Basic Medical Sciences, Nanchang Universitygrid.260463.5, Nanchang, China.
J Virol. 2022 Apr 27;96(8):e0201321. doi: 10.1128/jvi.02013-21. Epub 2022 Apr 7.
The high mutation rate of COVID-19 and the prevalence of multiple variants strongly support the need for pharmacological options to complement vaccine strategies. One region that appears highly conserved among different genera of coronaviruses is the substrate-binding site of the main protease (M or 3CL), making it an attractive target for the development of broad-spectrum drugs for multiple coronaviruses. PF-07321332, developed by Pfizer, is the first orally administered inhibitor targeting the main protease of SARS-CoV-2, which also has shown potency against other coronaviruses. Here, we report three crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and Middle East respiratory syndrome (MERS)-CoV bound to the inhibitor PF-07321332. The structures reveal a ligand-binding site that is conserved among SARS-CoV-2, SARS-CoV, and MERS-CoV, providing insights into the mechanism of inhibition of viral replication. The long and narrow cavity in the cleft between domains I and II of the main protease harbors multiple inhibitor-binding sites, where PF-07321332 occupies subsites S1, S2, and S4 and appears more restricted than other inhibitors. A detailed analysis of these structures illuminated key structural determinants essential for inhibition and elucidated the binding mode of action of the main proteases from different coronaviruses. Given the importance of the main protease for the treatment of SARS-CoV-2 infection, insights derived from this study should accelerate the design of safer and more effective antivirals. The current pandemic of multiple variants has created an urgent need for effective inhibitors of SARS-CoV-2 to complement vaccine strategies. PF-07321332, developed by Pfizer, is the first orally administered coronavirus-specific main protease inhibitor approved by the FDA. We solved the crystal structures of the main protease of SARS-CoV-2, SARS-CoV, and MERS-CoV that bound to the PF-07321332, suggesting PF-07321332 is a broad-spectrum inhibitor for coronaviruses. Structures of the main protease inhibitor complexes present an opportunity to discover safer and more effective inhibitors for COVID-19.
新型冠状病毒突变率高，多种变异株流行，这强烈支持我们需要药理学选择来补充疫苗策略。冠状病毒的不同属之间高度保守的一个区域是主蛋白酶（M 或 3CL）的底物结合位点，这使其成为开发针对多种冠状病毒的广谱药物的有吸引力的靶标。辉瑞公司开发的 PF-07321332 是第一种针对 SARS-CoV-2 主蛋白酶的口服抑制剂，它对其他冠状病毒也具有很强的抑制作用。在这里，我们报告了与抑制剂 PF-07321332 结合的 SARS-CoV-2、SARS-CoV 和中东呼吸综合征（MERS）-CoV 的主蛋白酶的三个晶体结构。这些结构揭示了主蛋白酶之间的配体结合位点在 SARS-CoV-2、SARS-CoV 和 MERS-CoV 中是保守的，为抑制病毒复制的机制提供了深入的了解。主蛋白酶 I 区和 II 区之间裂隙中的狭长腔容纳了多个抑制剂结合位点，PF-07321332 占据了亚结合位 S1、S2 和 S4，比其他抑制剂更受限制。对这些结构的详细分析阐明了抑制作用的关键结构决定因素，并阐明了不同冠状病毒主蛋白酶的结合模式。鉴于主蛋白酶在 SARS-CoV-2 感染治疗中的重要性，本研究的结果应该能够加速设计更安全、更有效的抗病毒药物。 当前多种变异株的大流行迫切需要有效的 SARS-CoV-2 抑制剂来补充疫苗策略。辉瑞公司开发的 PF-07321332 是 FDA 批准的第一种口服冠状病毒特异性主蛋白酶抑制剂。我们解决了与 PF-07321332 结合的 SARS-CoV-2、SARS-CoV 和 MERS-CoV 主蛋白酶的晶体结构，表明 PF-07321332 是一种广谱冠状病毒抑制剂。主蛋白酶抑制剂复合物的结构为发现更安全、更有效的 COVID-19 抑制剂提供了机会。
