Serine and threonine beta-lactones: a new class of hepatitis A virus 3C cysteine proteinase inhibitors.
Hepatitis A virus (HAV) 3C enzyme is a cysteine proteinase essential for viral replication and infectivity and represents a target for the development of antiviral drugs. A number of serine and threonine beta-lactones were synthesized and tested against HAV 3C proteinase. The D-N-Cbz-serine beta-lactone 5a displays competitive reversible inhibition with a K(i) value of 1.50 x 10(-6) M. Its enantiomer, L-N-Cbz-serine beta-lactone 5b is an irreversible inactivator with k(inact) = 0.70 min(-1), K(Iota) = 1.84 x 10(-4) M and k(inact)/K(Iota) = 3800 M(-1) min(-1). Mass spectrometry and HMQC NMR studies using (13)C-labeled 5b show that inactivation of the enzyme occurs by nucleophilic attack of the cysteine thiol (Cys-172) at the beta-position of the oxetanone ring. Although the N-Cbz-serine beta-lactones 5a and 5b display potent inhibition, other related analogues with an N-Cbz side chain, such as the five-membered ring homoserine gamma-lactones 14a and 14b, the four-membered ring beta-lactam 33, 2-methylene oxetane 34, cyclobutanone 36, and 3-azetidinone 39, fail to give significant inhibition of HAV 3C proteinase, thus demonstrating the importance of the beta-lactone ring for binding.
Lall
Manjinder S
MS
Department of Chemistry, University of Alberta, Edmonton, Alberta, Canada T6G 2G2.
Ramtohul
Yeeman K
YK
James
Michael N G
MN
Vederas
John C
JC
D000086042:3C Viral Proteases; D003500:Cyclization; D003546:Cysteine Endopeptidases; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000378:metabolism; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000494:pharmacology; D006507:Hepatovirus / Q000201:enzymology*; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D015394:Molecular Structure; D000077403:Orlistat; D012694:Serine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013912:Threonine / Q000737:chemistry*; D014764:Viral Proteins / Q000037:antagonists & inhibitors*
D015853:Cysteine Proteinase Inhibitors; D005231:Fatty Acids, Unsaturated; D007783:Lactones; C408995:N-benzyloxycarbonyl-serine-lactone; D014764:Viral Proteins; C117645:omuralide; C054282:antibiotic 1233A; D013912:Threonine; D012694:Serine; D000077403:Orlistat; D003546:Cysteine Endopeptidases; D000086042:3C Viral Proteases