Structure-based design and characterization of exocyclic peptidomimetics that inhibit TNFα binding to its receptor

被引：117

作者：

Takasaki, W ^{[1
]}

Kajino, Y ^{[1
]}

Kajino, K ^{[1
]}

Murali, R ^{[1
]}

Greene, MI ^{[1
]}

机构：

[1] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

来源：

NATURE BIOTECHNOLOGY | 1997年 / 15卷 / 12期

关键词：

rational drug design; TNF inhibitor; inflammation;

D O I：

10.1038/nbt1197-1266

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：

Exocyclic small peptidomimetics corresponding to three critical binding sites of tumor necrosis factor (TNF)-receptor(I) have been designed based on atomic features deduced from the crystal structures of TNF alpha. and the TNF beta/TNF-receptor(I) complex and a model of an anti-TNF alpha monoclonal antibody. TNF alpha antagonistic activities were evaluated by binding assays using soluble receptor or intact receptor on cells as well as an apoptosis/cytotoxicity assay. The most critical interaction site for rational design of peptidomimetics was localized to the loop1/domain3 of the TNF-receptor, The best antagonist showed 5 mu M inhibition in the binding assay, Biologically, the mimetics inhibited TNF alpha-mediated apoptosis.

引用

页码：1266 / 1270

页数：5

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