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

The main protease (M ) of coronaviruses plays a key role in viral replication, thus serving as a hot target for drug design. PF-00835231 is a promising inhibitor of SARS-CoV-2 M . Here, we report the inhibitory potency of PF-00835231 against SARS-CoV-2 M and seven M mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) from SARS-CoV-2 variants. The results confirm that PF-00835231 has broad-spectrum inhibition against various coronaviral M s. In addition, the crystal structures of SARS-CoV-2 M , SARS-CoV M , MERS-CoV M , and seven SARS-CoV-2 M mutants (G15S, M49I, Y54C, K90R, P132H, S46F, and V186F) in complex with PF-00835231 are solved. A detailed analysis of these structures reveals key determinants essential for inhibition and elucidates the binding modes of different coronaviral M s. Given the importance of the main protease for the treatment of coronaviral infection, structural insights into M inhibition by PF-00835231 can accelerate the design of novel antivirals with broad-spectrum efficacy against different human coronaviruses.