Synthesis and evaluation of keto-glutamine analogues as potent inhibitors of severe acute respiratory syndrome 3CLpro

被引:92
作者
Jain, RP
Pettersson, HI
Zhang, JM
Aull, KD
Fortin, PD
Huitema, C
Eltis, LD
Parrish, JC
James, MNG
Wishart, DS
Vederas, JC [1 ]
机构
[1] Univ Alberta, Dept Chem, Edmonton, AB T6G 2G2, Canada
[2] Univ British Columbia, Dept Microbiol, Vancouver, BC V6T 1Z3, Canada
[3] Univ British Columbia, Dept Biochem, Vancouver, BC V6T 1Z3, Canada
[4] Univ Alberta, Alberta Synchroton Inst, Edmonton, AB T6G 2E1, Canada
[5] Univ Alberta, Dept Biochem, Edmonton, AB T6G 2H7, Canada
[6] Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada
关键词
D O I
10.1021/jm0494873
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The 3C-like proteinase (3CL(pro)) of severe acute respiratory syndrome (SARS) coronavirus is a key target for structure-based drug design against this viral infection. The enzyme recognizes peptide substrates with a glutamine residue at the P1 site. A series of keto-glutamine analogues with a phthalhydrazido group at the a-position were synthesized and tested as reversible inhibitiors against SARS 3CL(pro). Attachment of tripeptide (Ac-Val-Thr-Leu) to these glutamine-based "warheads" generated significantly better inhibitors (4a-c, 8a-d) with IC50 values ranging from 0.60 to 70 muM.
引用
收藏
页码:6113 / 6116
页数:4
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