title: Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site.
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.
authors.affiliation: Novartis Pharma AG, Preclinical Research, Basel, Switzerland. gabrielle.weitz@pharma.novartis.com
authors.forename: G
authors.initials: G
authors.lastname: Weitz-Schmidt
authors.forename: K
authors.initials: K
authors.lastname: Welzenbach
authors.forename: V
authors.initials: V
authors.lastname: Brinkmann
authors.forename: T
authors.initials: T
authors.lastname: Kamata
authors.forename: J
authors.initials: J
authors.lastname: Kallen
authors.forename: C
authors.initials: C
authors.lastname: Bruns
authors.forename: S
authors.initials: S
authors.lastname: Cottens
authors.forename: Y
authors.initials: Y
authors.lastname: Takada
authors.forename: U
authors.initials: U
authors.lastname: Hommel
mesh_terms: D000495:Allosteric Site; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects*; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D039041:Integrin alpha4beta1; D016023:Integrins / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D016177:Macrophage-1 Antigen / Q000378:metabolism; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D016297:Mutagenesis, Site-Directed; D009281:Naphthalenes / Q000494:pharmacology* / Q000633:toxicity; D010538:Peritonitis / Q000188:drug therapy; D017035:Pravastatin / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D016201:Receptors, Lymphocyte Homing / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000502:physiology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D039041:Integrin alpha4beta1; D016023:Integrins; C430123:LFA703; D016169:Lymphocyte Function-Associated Antigen-1; D016177:Macrophage-1 Antigen; D009281:Naphthalenes; D016201:Receptors, Lymphocyte Homing; D018799:Intercellular Adhesion Molecule-1; D008148:Lovastatin; D017035:Pravastatin