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 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.
Weitz-Schmidt
G
G
Novartis Pharma AG, Preclinical Research, Basel, Switzerland. gabrielle.weitz@pharma.novartis.com
Welzenbach
K
K
Brinkmann
V
V
Kamata
T
T
Kallen
J
J
Bruns
C
C
Cottens
S
S
Takada
Y
Y
Hommel
U
U
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
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