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

Gabriele Weitz-Schmidt, Karl Welzenbach, Volker Brinkmann, Tetsji Kamata, Joerg Kallen, Christian Bruns, Sylvain Cottens, Yoshikazu Takada, Ulrich Hommel

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916 Citations (Scopus)

Abstract

The β2 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.

Original languageEnglish
Pages (from-to)687-692
Number of pages6
JournalNature medicine
Volume7
Issue number6
DOIs
Publication statusPublished - 2001 Jul 9
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Weitz-Schmidt, G., Welzenbach, K., Brinkmann, V., Kamata, T., Kallen, J., Bruns, C., Cottens, S., Takada, Y., & Hommel, U. (2001). Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nature medicine, 7(6), 687-692. https://doi.org/10.1038/89058