What's all the FLAP about?: 5-lipoxygenase-activating protein inhibitors for inflammatory diseases.
Leukotrienes have physiological roles in innate immune responses and pathological roles in inflammatory diseases, such as asthma, allergic rhinitis and atherosclerosis. Anti-leukotriene therapy has proven benefits in the treatment of respiratory disease, either through the inhibition of leukotriene synthesis or the selective antagonism of leukotriene receptors. The first committed step in the synthesis of leukotrienes is the oxidation of arachidonic acid (AA) by 5-lipoxygenase (5-LO), and the integral membrane protein 5-lipoxygenase-activating protein (FLAP) is an essential partner of 5-LO for this process. FLAP was molecularly identified via a photoaffinity probe and an affinity gel based on MK-886, a selective leukotriene inhibitor that has no activity against broken-cell preparations of 5-LO. Several FLAP inhibitors showed efficacy in early clinical trials in asthma but were not developed commercially for unpublished reasons. Recently, the FLAP (ALOX5AP) gene has been linked to risk for myocardial infarction, stroke and restenosis, reigniting pharmaceutical interest in this target. In addition, the recent determination of the crystal structure of inhibitor-bound FLAP offers exciting potential for novel FLAP inhibitor design.
Evans
Jilly F
JF
Amira Pharmaceuticals, 9535 Waples Street, San Diego, CA 92121, USA. jilly.evans@amiraphar.com
Ferguson
Andrew D
AD
Mosley
Ralph T
RT
Hutchinson
John H
JH
D058927:5-Lipoxygenase-Activating Proteins; D000818:Animals; D001249:Asthma / Q000188:drug therapy / Q000503:physiopathology; D002318:Cardiovascular Diseases / Q000188:drug therapy / Q000503:physiopathology; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D018849:Controlled Clinical Trials as Topic; D016503:Drug Delivery Systems; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D015289:Leukotrienes / Q000096:biosynthesis; D008565:Membrane Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D015289:Leukotrienes; D008565:Membrane Proteins