Inhibition of SARS-CoV 3CL protease by flavonoids

Jo, Seri; Kim, Suwon; Shin, Dong Hae; Kim, Mi-Sun

SARS-and MERS-CoVs genomes contain two open reading frames ORF1a and ORF1b translated to two respective viral polyproteins pp1a and pp1ab by host ribosomes. ORF1a encodes two cysteine proteases, a papain-like protease (PLpro) and a 3C-like protease (3CLpro). While PLpro cuts the first three cleavage sites of its polyprotein, 3CLpro is responsible for cleavage of the remaining 11 locations resulting in release of a total of 16 nonstructural proteins (nsp) in both SARS-and MERS-CoVs. The homodimeric form of 3CLpro is active in the presence of substrates. The crystal structures of both 3CLpros showed that each monomer is composed of three structural domains: domains I and II form a chymotrypsin-like architecture with a catalytic cysteine and are connected to a third C-terminal domain via a long loop 10 . In the proteolytic site, all 3CLpros prefer glutamine at P1 position and leucine, basic residues, small hydrophobic residues at P2, P3 and P4 positions, respectively 11 . At P1 0 and P2 0 positions, small residues are required. However, P3 0 position shows no strong preference. Since the autocleavage process is essential for viral propagation, 3CLpro is a good drug target for anti-coronaviral infection.