Crystal Structures of Inhibitor-Bound Main Protease from Delta- and Gamma-Coronaviruses

Abstract

With the spread of SARS-CoV-2 throughout the globe causing 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 a 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 the beluga whale. A comparison with the apo structure of SW1 Mpro, which is also presented here, enabled the identification of structural arrangements upon inhibitor binding at the active site. The cocrystal structures reveal binding modes and interactions of two covalent inhibitors, PF-00835231 (active form of lufotrelvir) bound to HKU15, and GC376 bound to SW1 Mpro. These structures may be leveraged to target diverse coronaviruses and toward the structure-based design of pan-CoV inhibitors.

Structural basis for the inhibition of coronaviral main proteases by PF-00835231

“…The binding pattern of PF-00835231 with SARS-CoV-2 M pro is highly similar, except the binding mode of the indole group. The covalent binding was not found between the indole group of PF-00835231 and Thr190 of main protease in previous studies [16,26].…”

“…Previous reports also solved the crystal structure of the SARS-CoV-2 M pro in complex with PF-00835231 (PDB ID 8DSU and 6XHM) [16,26]. By superimposing the previously solved structures of SARS-CoV-2 M pro -PF-00835231 complex with the structure reported in this study (Figure S1), the RMSD on the 433 optimally arranged Cα atoms were 0.53 Å (PDB ID 8DSU) and 0.653 Å (PDB ID 6XHM), respectively.…”