Journal
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS
Volume 421, Issue 2, Pages 207-216Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.abb.2003.11.013
Keywords
slow-binding inhibition; peptidyl-alpha-ketoamide; hepatitis C virus NS3 serine protease; conformational changes; association rate constant; dissociation rate constant; oxyanion
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A series of novel peptidyl-alpha-ketoamide compounds were evaluated as inhibitors of the DeltaNS3-NS4A serine protease from the hepatitis C virus. These peptidyl-alpha-ketoamide inhibitors with K-i values ranging from 0.17 nM to 5.6 muM exhibited slow-binding inhibition. Kinetic studies established one-step kinetic mechanisms and dissociation rate constants in the 3-7 x 10(-5) s(-1) range for these compounds. The association rate constants, which ranged from 10 to 263,000 M-1 s(-1), were responsible for the greater than four order of magnitude overall binding affinity range exhibited by this series. An X-ray crystal structure of a protease-inhibitor complex revealed an unusual interaction between the oxyanion of the adduct and the protein as well as a significant movement in the Sl' region of the protein loop comprising residues 35-42. These results are quite different from peptidyl-alpha-ketoacid inhibition of HCV protease, which reportedly undergoes no notable conformational changes and proceeds with a two-step slow-binding kinetic mechanism. (C) 2003 Elsevier Inc. All rights reserved.
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