Coronavirus Main Proteinase (3CL ^pro ) Structure: Basis for Design of Anti-SARS Drugs

A novel coronavirus has been identified as the causative agent of severe acute respiratory syndrome (SARS). The viral main proteinase (M ^pro , also called 3CL ^pro ), which controls the activities of the coronavirus replication complex, is an attractive target for therapy. We determined crystal structures for human coronavirus (strain 229E) M ^pro and for an inhibitor complex of porcine coronavirus [transmissible gastroenteritis virus (TGEV)] M ^pro , and we constructed a homology model for SARS coronavirus (SARS-CoV) M ^pro . The structures reveal a remarkable degree of conservation of the substrate-binding sites, which is further supported by recombinant SARS-CoV M ^pro -mediated cleavage of a TGEV M ^pro substrate. Molecular modeling suggests that available rhinovirus 3C ^pro inhibitors may be modified to make them useful for treating SARS.