Structure-Based Optimization of a Peptidyl Inhibitor against Calcineurin-Nuclear Factor of Activated T Cell (NFAT) Interaction

被引：8

作者：

Qian, Ziqing ^{[1
]}

Dougherty, Patrick G. ^{[1
]}

Liu, Tao ^{[1
]}

Oottikkal, Shameema ^{[1
]}

Hogan, Patrick G. ^{[2
]}

Hadad, Christopher M. ^{[1
]}

Pei, Dehua ^{[1
]}

机构：

[1] Ohio State Univ, Dept Chem & Biochem, Columbus, OH 43210 USA

[2] La Jolla Inst Allergy & Immunol, Div Signaling & Gene Express, La Jolla, CA 92037 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 18期

基金：

美国国家卫生研究院;

关键词：

PSEUDO-PROLINES; CYCLOSPORINE; POTENT; TRANSPLANTATION; PROTEASE; COMPLEX; BINDING; TARGET;

D O I：

10.1021/jm500743t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Calcineurin inhibitors such as cyclosporine A and FK506 are effective immunosuppressants but produce severe side effects. Rational modification of a previously reported peptide inhibitor, GPHPVIVITGPHEE (K-D similar to 500 nM), by replacing the two valine residues with tert-leucine and the C-terminal proline with a cis-proline analogue, gave an improved inhibitor ZIZIT-cisPro, which binds to calcineurin with a K-D value of 2.6 nM and is more resistant to proteolysis.

引用

页码：7792 / 7797

页数：6

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