Abstract
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 (Mpro) plays an essential role in viral replication, making it an ideal target for drug development. However, the structure of the Deltacoronavirus Mpro 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 Mpro complexed with a Michael acceptor inhibitor. Structural comparison showed that the backbone of PDCoV Mpro is similar to those of alpha-, beta- and gamma-CoV Mpros. The substrate-binding pocket of Mpro is well conserved in the subfamily Coronavirinae. In addition, we also observed that Mpros from the same genus adopted a similar conformation. Furthermore, the structure of PDCoV Mpro in complex with a Michael acceptor inhibitor revealed the mechanism of its inhibition of PDCoV Mpro. Our results provide a basis for the development of broad-spectrum antivirals against PDCoV and other CoVs.
Highlights
Coronaviruses (CoVs) are round or oval enveloped viruses with a positive-sense RNA genome [1]
It has been demonstrated that porcine deltacoronavirus (PDCoV) can infect cells of human origin by interacting with host aminopeptidase N (APN) via its spike (S) protein, and studies have identified children in Haiti who were positive for Porcine deltacoronavirus (PDCoV), which poses a considerable concern to human health with adaptive changes [30,31]
The PDCoV main protease (Mpro) coding sequence was cloned into the BamHI and XhoI restriction sites of the pET-28b_SUMO vector and transformed into Escherichia coli strain BL21 (DE3)
Summary
Coronaviruses (CoVs) are round or oval enveloped viruses with a positive-sense RNA genome [1]. It is necessary to develop broad-spectrum antivirals against existing and emerging CoVs. CoV main proteases (Mpros), called 3C-like proteases, which play a vital role in the proteolytic pathway in viral replication, are known to be among the most attractive and ideal targets for antiviral drug design [15]. It has been demonstrated that porcine deltacoronavirus (PDCoV) can infect cells of human origin by interacting with host aminopeptidase N (APN) via its spike (S) protein, and studies have identified children in Haiti who were positive for PDCoV, which poses a considerable concern to human health with adaptive changes [30,31]. We determined the crystal structure of PDCoV Mpro from Deltacoronavirus complexed with a peptidomimetic inhibitor with a Michael acceptor, which is the substituent group on the activated α, β unsaturated ester and can undergo Michael addition reaction with nucleophile from the enzyme. Viruses 2022, 14, 486 peptidomimetic inhibitors carrying a Michael acceptor warhead are effective against the Mpros of all CoVs
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