rupintrivir and Severe-Acute-Respiratory-Syndrome

Topics: Binding Sites; Coronavirus 3C Proteases; Cysteine Endopeptidases; Humans; Isoxazoles; Phenylalanine; Protease Inhibitors; Protein Structure, Tertiary; Pyrrolidinones; Rhinovirus; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Valine; Viral Proteins

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

Topics: Amino Acid Chloromethyl Ketones; Amino Acid Sequence; Antiviral Agents; Binding Sites; Catalytic Domain; Coronavirus 229E, Human; Coronavirus 3C Proteases; Crystallization; Crystallography, X-Ray; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Dimerization; Drug Design; Humans; Isoxazoles; Models, Molecular; Molecular Sequence Data; Phenylalanine; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Pyrrolidinones; Recombinant Proteins; Sequence Alignment; Sequence Homology, Amino Acid; Severe Acute Respiratory Syndrome; Severe acute respiratory syndrome-related coronavirus; Transmissible gastroenteritis virus; Valine