Lymphocyte function-associated antigen-1 blockade by statins: molecular basis and biological relevance.
Lymphocyte function-associated antigen-1 (LFA-1) belongs to the integrin family and plays an important role in leukocyte trafficking and in T-cell activation. Random screening of chemical libraries identified the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor lovastatin as an inhibitor of the LFA-1/intercellular adhesion molecule (ICAM)-1 interaction. The effect of lovastatin on LFA-1 was found to be unrelated to the inhibition of HMG-CoA reductase and to be mediated by lovastatin binding to a novel allosteric site within LFA-1. The biological relevance of LFA-1 inhibition by statins with respect to the overall benefit of this drug class is reviewed. The implications of the statin effect on LFA-1 for future drug design and therapy are discussed.
Weitz-Schmidt
Gabriele
G
Novartis Pharma AG, Preclinical Research, Basel, Switzerland. gabriele.weitz@pharma.novartis.com
D000276:Adjuvants, Immunologic / Q000378:metabolism / Q000494:pharmacology; D000495:Allosteric Site / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002318:Cardiovascular Diseases / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D002448:Cell Adhesion / Q000187:drug effects* / Q000502:physiology; D002634:Chemotaxis, Leukocyte / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D016023:Integrins / Q000187:drug effects / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects* / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000187:drug effects* / Q000378:metabolism
D000276:Adjuvants, Immunologic; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D016023:Integrins; D016169:Lymphocyte Function-Associated Antigen-1; D018799:Intercellular Adhesion Molecule-1