Synthesis and evaluation of keto-glutamine analogues as inhibitors of hepatitis A virus 3C proteinase.
Hepatitis A virus (HAV) 3C enzyme is a picornaviral cysteine proteinase involved in the processing of the initially synthesized viral polyprotein and is therefore important for viral maturation and infectivity. Although it is a cysteine proteinase, this enzyme has a topology similar to those of the chymotrypsin-like serine proteinases. Since the enzyme recognizes peptide substrates with a glutamine residue at the P(1) site, a number of ketone-containing glutamine compounds analogous to nanomolar inhibitors of cathepsin K were synthesized and tested for inhibition against HAV 3C proteinase. In addition, a 3-azetidinone scaffold was incorporated into the glutamine fragment but gave only modest inhibition. However, introduction of a phthalhydrazido group alpha to the ketone moiety gave significantly better inhibitors with IC(50) values ranging from 13 to 164 microM, presumably due to the effect of intramolecular hydrogen bonding to the ketone. In addition, the tetrapeptide phthalhydrazide 24 was found to be a competitive reversible inhibitor (K(i) = 9 x 10(-6) M) and also showed no loss of inhibitory potency in the presence of dithiothreitol.
Ramtohul
Yeeman K
YK
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada.
James
Michael N G
MN
Vederas
John C
JC
D000086042:3C Viral Proteases; D001665:Binding Sites / Q000187:drug effects; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D005973:Glutamine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D030041:Hepatitis A virus / Q000201:enzymology*; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D009842:Oligopeptides / Q000138:chemical synthesis; D013329:Structure-Activity Relationship; D014764:Viral Proteins
D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D014764:Viral Proteins; C466838:acetyl-leucyl-alanyl-alanyl-OH; D005973:Glutamine; D002403:Cathepsins; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases; D056657:Cathepsin K