1rgq Citations

Hepatitis C NS3 protease inhibition by peptidyl-alpha-ketoamide inhibitors: kinetic mechanism and structure.

Arch Biochem Biophys 421 207-16 (2004)
Cited: 11 times
EuropePMC logo PMID: 14984200

Abstract

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 Ki values ranging from 0.17 nM to 5.6 microM 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 S1' 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.

Articles - 1rgq mentioned but not cited (3)

  1. Multiple origins of viral capsid proteins from cellular ancestors. Krupovic M, Koonin EV. Proc. Natl. Acad. Sci. U.S.A. 114 E2401-E2410 (2017)
  2. Identification of HCV protease inhibitor resistance mutations by selection pressure-based method. Qiu P, Sanfiorenzo V, Curry S, Guo Z, Liu S, Skelton A, Xia E, Cullen C, Ralston R, Greene J, Tong X. Nucleic Acids Res. 37 e74 (2009)
  3. Structure of Leishmania major methionyl-tRNA synthetase in complex with intermediate products methionyladenylate and pyrophosphate. Larson ET, Kim JE, Zucker FH, Kelley A, Mueller N, Napuli AJ, Verlinde CL, Fan E, Buckner FS, Van Voorhis WC, Merritt EA, Hol WG. Biochimie 93 570-582 (2011)


Reviews citing this publication (3)

Articles citing this publication (5)

  1. Exploration of acyl sulfonamides as carboxylic acid replacements in protease inhibitors of the hepatitis C virus full-length NS3. Rönn R, Sabnis YA, Gossas T, Akerblom E, Danielson UH, Hallberg A, Johansson A. Bioorg. Med. Chem. 14 544-559 (2006)
  2. General and Modular Strategy for Designing Potent, Selective, and Pharmacologically Compliant Inhibitors of Rhomboid Proteases. Tichá A, Stanchev S, Vinothkumar KR, Mikles DC, Pachl P, Began J, Škerle J, Švehlová K, Nguyen MTN, Verhelst SHL, Johnson DC, Bachovchin DA, Lepšík M, Majer P, Strisovsky K. Cell Chem Biol 24 1523-1536.e4 (2017)
  3. Novel Peptidomimetic Hepatitis C Virus NS3/4A Protease Inhibitors Spanning the P2-P1' Region. Lampa AK, Bergman SM, Gustafsson SS, Alogheli H, Akerblom EB, Lindeberg GG, Svensson RM, Artursson P, Danielson UH, Karlén A, Sandström A. ACS Med Chem Lett 5 249-254 (2014)
  4. Can Relative Binding Free Energy Predict Selectivity of Reversible Covalent Inhibitors? Chatterjee P, Botello-Smith WM, Zhang H, Qian L, Alsamarah A, Kent D, Lacroix JJ, Baudry M, Luo Y. J. Am. Chem. Soc. 139 17945-17952 (2017)
  5. Rapid synthesis of internal peptidyl α-ketoamides by on resin oxidation for the construction of rhomboid protease inhibitors. Van Kersavond T, Konopatzki R, van der Plassche MAT, Yang J, Verhelst SHL. RSC Adv 11 4196-4199 (2021)