PT  - JOURNAL ARTICLE
AU  - Sarah N. Zvornicanin
AU  - Ala M. Shaqra
AU  - Qiu Yu J. Huang
AU  - Elizabeth Ornelas
AU  - Mallika Moghe
AU  - Mark Knapp
AU  - Stephanie Moquin
AU  - Dustin Dovala
AU  - Celia A. Schiffer
AU  - Nese Kurt Yilmaz
TI  - Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses
AID  - 10.1101/2023.02.01.526623
DP  - 2023 Jan 01
TA  - bioRxiv
PG  - 2023.02.01.526623
4099  - http://biorxiv.org/content/early/2023/02/02/2023.02.01.526623.short
4100  - http://biorxiv.org/content/early/2023/02/02/2023.02.01.526623.full
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.