In situ assembly of enzyme inhibitors using extended tethering

被引：159

作者：

Erlanson, DA ^{[1
]}

Lam, JW ^{[1
]}

Wiesmann, C ^{[1
]}

Luong, TN ^{[1
]}

Simmons, RL ^{[1
]}

DeLano, WL ^{[1
]}

Choong, IC ^{[1
]}

Burdett, MT ^{[1
]}

Flanagan, WM ^{[1
]}

Lee, D ^{[1
]}

Gordon, EM ^{[1
]}

O'Brien, T ^{[1
]}

机构：

[1] Sunesis Pharmaceut Inc, San Francisco, CA 94080 USA

来源：

NATURE BIOTECHNOLOGY | 2003年 / 21卷 / 03期

关键词：

D O I：

10.1038/nbt786

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Cysteine aspartyl protease-3 (caspase-3) is a mediator of apoptosis and a therapeutic target for a wide range of diseases. Using a dynamic combinatorial technology, 'extended tethering', we identified unique nonpeptidic inhibitors for this enzyme. Extended tethering allowed the identification of ligands that bind to discrete regions of caspase-3 and also helped direct the assembly of these ligands into small-molecule inhibitors. We first designed a small-molecule 'extender' that irreversibly alkylates the cysteine residue of caspase-3 and also contains a thiol group. The modified protein was then screened against a library of disulfide-containing small-molecule fragments. Mass-spectrometry was used to identify ligands that bind noncovalently to the protein and that also form a disulfide linkage with the extender. Linking the selected fragments with binding elements from the extenders generates reversible, tight-binding molecules that are druglike and distinct from known inhibitors. One molecule derived from this approach inhibited apoptosis in cells.

引用

页码：308 / 314

页数：7

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