Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site

被引：865

作者：

Weitz-Schmidt, G ^{[1
]}

Welzenbach, K

Brinkmann, V

Kamata, T

Kallen, J

Bruns, C

Cottens, S

Takada, Y

Hommel, U

机构：

[1] Novartis Pharma AG, Preclin Res, Basel, Switzerland

[2] Scripps Res Inst, Dept Vasc Biol, La Jolla, CA USA

来源：

NATURE MEDICINE | 2001年 / 7卷 / 06期

关键词：

D O I：

10.1038/89058

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

The beta2 integrin leukocyte function antigen-1 (LFA-1) has an important role in the pathophysiology of inflammatory and autoimmune diseases. Here we report that statin compounds commonly used for the treatment of hypercholesterolemia selectively blocked LFA-1-mediated adhesion and costimulation of lymphocytes. This effect was unrelated to the statins' inhibition of 3-hydroxy-3-methylglutaryl coenzyme-A reductase; instead it occurred via binding to a novel allosteric site within LFA-1. Subsequent optimization of the statins for LFA-1 binding resulted in potent, selective and orally active LFA-1 inhibitors that suppress the inflammatory response in a murine model of peritonitis. Targeting of the statin-binding site of LFA-1 could be used to treat diseases such as psoriasis, rheumatoid arthritis, ischemia/reperfusion injury and transplant rejection.

引用

页码：687 / 692

页数：6

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