Beta-lactones as a new class of cysteine proteinase inhibitors: inhibition of hepatitis A virus 3C proteinase by N-Cbz-serine beta-lactone.
[reaction: see text] N-Benzyloxycarbonyl-L-serine beta-lactone (1) is shown to irreversibly inactivate the 3C cysteine proteinase of hepatitis A virus (HAV) with k(inact) = 0.70 min(-1), K(I) = 1.84 x 10(-4) M and k(inact)/K(I) = 3800 M(-1) min(-1) at an enzyme concentration of 0.1 microM. Mass spectrometric and HMQC NMR studies using 13C-labeled 1 show that the active site cysteine (Cys-172) thiol of the HAV 3C proteinase attacks the beta-position (i.e. C-4) of the oxetanone ring, thereby leading to ring opening and alkylation of the sulfur. In contrast, the enantiomer of this beta-lactone, 2, is a reversible competitive inhibitor (Ki = 1.50 x 10(-6) M) at similar enzyme concentrations. The beta-lactone motif represents a new class of inhibitors of cysteine proteinases.
Lall
M S
MS
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Karvellas
C
C
Vederas
J C
JC
D000086042:3C Viral Proteases; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D012694:Serine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D015853:Cysteine Proteinase Inhibitors; D007783:Lactones; C408995:N-benzyloxycarbonyl-serine-lactone; D014764:Viral Proteins; D012694:Serine; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases