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Nat Med. 2001 Jun;7(6):687-92.

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

Author information

  • 1Novartis Pharma AG, Preclinical Research, Basel, Switzerland. gabrielle.weitz@pharma.novartis.com

Abstract

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.

PMID:
11385505
[PubMed - indexed for MEDLINE]
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