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

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