RT Journal Article
SR Electronic
T1 Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.02.01.526623
DO 10.1101/2023.02.01.526623
A1 Sarah N. Zvornicanin
A1 Ala M. Shaqra
A1 Qiu Yu J. Huang
A1 Elizabeth Ornelas
A1 Mallika Moghe
A1 Mark Knapp
A1 Stephanie Moquin
A1 Dustin Dovala
A1 Celia A. Schiffer
A1 Nese Kurt Yilmaz
YR 2023
UL http://biorxiv.org/content/early/2023/02/02/2023.02.01.526623.abstract
AB With the spread of SARS-CoV-2 throughout the globe to cause 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 potential zoonotic transmission threat. Here, we determined the inhibitor-bound crystal structures of the main protease (Mpro) from the delta-CoV porcine HKU15 and gamma-CoV SW1 from beluga whale. Comparison with the apo structure of SW1 Mpro, which we also present here, enabled identifying structural arrangements upon inhibitor binding at the active site. The binding modes and interactions of two covalent inhibitors, PF-00835231 (lufotrelvir) bound to HKU15 and GC376 bound to SW1 Mpro, reveal features that may be leveraged to target diverse coronaviruses and toward structure-based design of pan-CoV inhibitors.Competing Interest StatementThis research received no external funding. The research at CAS laboratory was funded by Novartis Institutes for Biomedical Research.