title: Inhibition of the hepatitis C virus NS3/4A protease. The crystal structures of two protease-inhibitor complexes.
abstract: The hepatitis C virus NS3 protein contains a serine protease domain with a chymotrypsin-like fold, which is a target for development of therapeutics. We report the crystal structures of this domain complexed with NS4A cofactor and with two potent, reversible covalent inhibitors spanning the P1-P4 residues. Both inhibitors bind in an extended backbone conformation, forming an anti-parallel beta-sheet with one enzyme beta-strand. The P1 residue contributes most to the binding energy, whereas P2-P4 side chains are partially solvent exposed. The structures do not show notable rearrangements of the active site upon inhibitor binding. These results are significant for the development of antivirals.
authors.affiliation: Biotechnology, Via Pontina Km 30.600, 00040 Pomezia, Rome, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Di Marco
authors.forename: M
authors.initials: M
authors.lastname: Rizzi
authors.forename: C
authors.initials: C
authors.lastname: Volpari
authors.forename: M A
authors.initials: MA
authors.lastname: Walsh
authors.forename: F
authors.initials: F
authors.lastname: Narjes
authors.forename: S
authors.initials: S
authors.lastname: Colarusso
authors.forename: R
authors.initials: R
authors.lastname: De Francesco
authors.forename: V G
authors.initials: VG
authors.lastname: Matassa
authors.forename: M
authors.initials: M
authors.lastname: Sollazzo
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry*; D001665:Binding Sites; D003460:Crystallization; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology*; D006860:Hydrogen Bonding; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000998:Antiviral Agents; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases