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

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.