Serine and threonine β-lactones:: A new class of hepatitis a virus 3C cysteine proteinase inhibitors

被引:91
作者
Lall, MS
Ramtohul, YK
James, MNG
Vederas, JC [1 ]
机构
[1] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada
[2] Univ Alberta, Dept Biochem, CIHR Grp Prot Struct & Funct, Edmonton, AB T6G 2H7, Canada
关键词
D O I
10.1021/jo0109016
中图分类号
O62 [有机化学];
学科分类号
070303 ; 081704 ;
摘要
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 0.70 min(-1), K, = 1.84 x 10(-4) M and k(inact)/K-I = 3800 M-1 min(-1). Mass spectrometry and HMQC NMR studies using C-13-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.
引用
收藏
页码:1536 / 1547
页数:12
相关论文
共 71 条