Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA.
Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA.
Viruses. 2023 Mar 18;15(3):781. doi: 10.3390/v15030781.
With the spread of SARS-CoV-2 throughout the globe causing the COVID-19 pandemic, the threat of zoonotic transmissions of coronaviruses (CoV) has become even more evident. As human infections have been caused by alpha- and beta-CoVs, structural characterization and inhibitor design mostly focused on these two genera. However, viruses from the delta and gamma genera also infect mammals and pose a potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (M) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from the beluga whale. A comparison with the apo structure of SW1 M, which is also presented here, enabled the identification of structural arrangements upon inhibitor binding at the active site. The cocrystal structures reveal binding modes and interactions of two covalent inhibitors, PF-00835231 (active form of lufotrelvir) bound to HKU15, and GC376 bound to SW1 M. These structures may be leveraged to target diverse coronaviruses and toward the structure-based design of pan-CoV inhibitors.
随着 SARS-CoV-2 在全球范围内的传播导致 COVID-19 大流行，人畜共患冠状病毒（CoV）传播的威胁变得更加明显。由于人类感染是由α和β冠状病毒引起的，因此结构特征和抑制剂设计主要集中在这两个属上。然而，来自德尔塔和伽马属的病毒也感染哺乳动物，并构成潜在的人畜共患传播威胁。在这里，我们确定了来自猪 HKU15 的德尔塔-CoV 和来自白鲸的 SW1 的γ-CoV 的主要蛋白酶（M）的抑制剂结合晶体结构。与这里还呈现的 SW1 M 的 apo 结构进行比较，能够识别在活性部位结合抑制剂时的结构排列。共晶结构揭示了两种共价抑制剂的结合模式和相互作用，PF-00835231（lufotrelvir 的活性形式）与 HKU15 结合，以及 GC376 与 SW1 M 结合。这些结构可以被利用来靶向不同的冠状病毒，并针对泛冠状病毒抑制剂进行基于结构的设计。
