Open AccessRecognition of Divergent Viral Substrates by the SARS-CoV-2 Main Protease
Author(s) -
Elizabeth A. MacDonald,
Gary Frey,
Mark Namchuk,
Stephen C. Harrison,
Stephen M Hinshaw,
Ian W. Windsor
Publication year - 2021
Publication title -
acs infectious diseases
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.324
H-Index - 39
ISSN - 2373-8227
DOI - 10.1021/acsinfecdis.1c00237
Subject(s) - proteases , protease , coronavirus , cleavage (geology) , biology , viral replication , virology , peptide sequence , virus , chemistry , biochemistry , covid-19 , enzyme , infectious disease (medical specialty) , gene , medicine , disease , paleontology , pathology , fracture (geology)
The main protease (M pro ) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease (COVID-19), is an ideal target for pharmaceutical inhibition. M pro is conserved among coronaviruses and distinct from human proteases. Viral replication depends on the cleavage of the viral polyprotein at multiple sites. We present crystal structures of SARS-CoV-2 M pro bound to two viral substrate peptides. The structures show how M pro recognizes distinct substrates and how subtle changes in substrate accommodation can drive large changes in catalytic efficiency. One peptide, constituting the junction between viral nonstructural proteins 8 and 9 (nsp8/9), has P1' and P2' residues that are unique among the SARS-CoV-2 M pro cleavage sites but conserved among homologous junctions in coronaviruses. M pro cleaves nsp8/9 inefficiently, and amino acid substitutions at P1' or P2' can enhance catalysis. Visualization of M pro with intact substrates provides new templates for antiviral drug design and suggests that the coronavirus lifecycle selects for finely tuned substrate-dependent catalytic parameters.