The Structure of the Porcine Deltacoronavirus Main Protease Reveals a Conserved Target for the Design of Antivirals

VIRUSES-BASEL(2022)

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摘要
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-pro) plays an essential role in viral replication, making it an ideal target for drug development. However, the structure of the Deltacoronavirus M-pro is still unavailable. Porcine deltacoronavirus (PDCoV) is a novel CoV that belongs to the genus Deltacoronavirus and causes atrophic enteritis, severe diarrhea, vomiting and dehydration in pigs. Here, we determined the structure of PDCoV M-pro complexed with a Michael acceptor inhibitor. Structural comparison showed that the backbone of PDCoV M-pro is similar to those of alpha-, beta- and gamma-CoV M(pro)s. The substrate-binding pocket of M-pro is well conserved in the subfamily Coronavirinae. In addition, we also observed that M(pro)s from the same genus adopted a similar conformation. Furthermore, the structure of PDCoV M-pro in complex with a Michael acceptor inhibitor revealed the mechanism of its inhibition of PDCoV M-pro. Our results provide a basis for the development of broad-spectrum antivirals against PDCoV and other CoVs.
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关键词
coronaviruses, porcine deltacoronavirus, main protease, broad-spectrum antivirals
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