Inhibition of the hepatitis C virus NS3/4A protease. The crystal structures of two protease-inhibitor complexes.
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Di Marco S, Rizzi M, Volpari C, Walsh MA, Narjes F, Colarusso S, De Francesco R, Matassa VG, Sollazzo M
Inhibition of the hepatitis C virus NS3/4A protease. The crystal structures of two protease-inhibitor complexes.
J Biol Chem. 2000 Mar 10;275(10):7152-7.
- PubMed ID
- 10702283 [ View in PubMed]
- 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.