Lu Jimmy, Chen Sizhu Amelia, Khan Muhammad Bashir, Brassard Raelynn, Arutyunova Elena, Lamer Tess, Vuong Wayne, Fischer Conrad, Young Howard S, Vederas John C, Lemieux M Joanne
Department of Biochemistry, University of Alberta, Edmonton, AB, Canada.
Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada.
Front Chem. 2022 Feb 24;10:852210. doi: 10.3389/fchem.2022.852210. eCollection 2022.
Coronaviruses infect a variety of hosts in the animal kingdom, and while each virus is taxonomically different, they all infect their host the same mechanism. The coronavirus main protease (M, also called 3CL), is an attractive target for drug development due to its essential role in mediating viral replication and transcription. An M inhibitor, GC376, has been shown to treat feline infectious peritonitis (FIP), a fatal infection in cats caused by internal mutations in the feline enteric coronavirus (FECV). Recently, our lab demonstrated that the feline drug, GC373, and prodrug, GC376, are potent inhibitors of SARS-CoV-2 M and solved the structures in complex with the drugs; however, no crystal structures of the FIP virus (FIPV) M with the feline drugs have been published so far. Here, we present crystal structures of FIPV M-GC373/GC376 complexes, revealing the inhibitors covalently bound to Cys144 in the active site, similar to SARS-CoV-2 M. Additionally, GC376 has a higher affinity for FIPV M with lower nanomolar K values compared to SARS-CoV and SARS-CoV-2 M. We also show that improved derivatives of GC376 have higher potency for FIPV M. Since GC373 and GC376 represent strong starting points for structure-guided drug design, determining the crystal structures of FIPV M with these inhibitors are important steps in drug optimization and structure-based broad-spectrum antiviral drug discovery.
冠状病毒可感染动物界的多种宿主，尽管每种病毒在分类学上有所不同，但它们感染宿主的机制相同。冠状病毒主要蛋白酶（M，也称为3CL），由于其在介导病毒复制和转录中起关键作用，是药物开发的一个有吸引力的靶点。一种M抑制剂GC376已被证明可治疗猫传染性腹膜炎（FIP），这是一种由猫肠道冠状病毒（FECV）内部突变引起的猫致命感染。最近，我们实验室证明，猫用药物GC373和前药GC376是严重急性呼吸综合征冠状病毒2（SARS-CoV-2）M的有效抑制剂，并解析了与这些药物结合的复合物结构；然而，迄今为止，尚未发表FIP病毒（FIPV）M与猫用药物的晶体结构。在此，我们展示了FIPV M-GC373/GC376复合物的晶体结构，揭示了抑制剂与活性位点中的半胱氨酸144共价结合，这与SARS-CoV-2 M相似。此外，与SARS-CoV和SARS-CoV-2 M相比，GC376对FIPV M具有更高的亲和力，其K值处于较低的纳摩尔水平。我们还表明，GC376的改进衍生物对FIPV M具有更高的效力。由于GC373和GC376是结构导向药物设计的有力起点，确定FIPV M与这些抑制剂的晶体结构是药物优化和基于结构的广谱抗病毒药物发现的重要步骤。
