School of Life Sciences, Tianjin University, Tianjin 300072, China.
Tianjin International Joint Academy of Biotechnology and Medicine, Tianjin 300457, China.
Viruses. 2022 Feb 27;14(3):486. doi: 10.3390/v14030486.
The existing zoonotic coronaviruses (CoVs) and viral genetic variants are important microbiological pathogens that cause severe disease in humans and animals. Currently, no effective broad-spectrum antiviral drugs against existing and emerging CoVs are available. The CoV main protease (M) plays an essential role in viral replication, making it an ideal target for drug development. However, the structure of the M is still unavailable. Porcine deltacoronavirus (PDCoV) is a novel CoV that belongs to the genus and causes atrophic enteritis, severe diarrhea, vomiting and dehydration in pigs. Here, we determined the structure of PDCoV M complexed with a Michael acceptor inhibitor. Structural comparison showed that the backbone of PDCoV M is similar to those of alpha-, beta- and gamma-CoV Ms. The substrate-binding pocket of M is well conserved in the subfamily . In addition, we also observed that Ms from the same genus adopted a similar conformation. Furthermore, the structure of PDCoV M in complex with a Michael acceptor inhibitor revealed the mechanism of its inhibition of PDCoV M. Our results provide a basis for the development of broad-spectrum antivirals against PDCoV and other CoVs.
现有的人畜共患冠状病毒（CoVs）和病毒遗传变异体是重要的微生物病原体，可导致人类和动物严重疾病。目前，尚无针对现有和新兴 CoVs 的有效广谱抗病毒药物。CoV 主要蛋白酶（M）在病毒复制中起着至关重要的作用，使其成为药物开发的理想靶点。然而，M 的结构仍然未知。猪德尔塔冠状病毒（PDCoV）是一种新型 CoV，属于属，可导致猪萎缩性肠炎、严重腹泻、呕吐和脱水。在这里，我们确定了 PDCoV M 与迈克尔受体抑制剂复合物的结构。结构比较表明，PDCoV M 的骨架与α、β和γ-CoV M 相似。M 的底物结合口袋在亚科中高度保守。此外，我们还观察到来自同一属的 Ms 采用了相似的构象。此外，PDCoV M 与迈克尔受体抑制剂复合物的结构揭示了其抑制 PDCoV M 的机制。我们的研究结果为开发针对 PDCoV 和其他 CoV 的广谱抗病毒药物提供了依据。
