Alpha 4 integrin antagonists.
The accumulation of leukocytes in various organs contributes to the pathogenesis of a number of human autoimmune diseases such as asthma, rheumatoid arthritis, Crohn s disease, ulcerative colitis, hepatitis C, and multiple sclerosis. The inflammatory processes leading to tissue damage and disease are mediated in part by the alpha4 integrins, alpha4beta1 and alpha4beta7, expressed on the leukocyte cell surface. These glycoprotein receptors modulate cell adhesion via interaction with their primary ligands, vascular cell adhesion molecule (VCAM) and mucosal addressin cell adhesion molecule (MAdCAM), expressed in the affected tissue. Upon binding, the combined integrin/CAM interactions at the cell surface result in firm adhesion of the leukocyte to the vessel wall followed by entry into the affected tissue. Elevated cell adhesion molecule (CAM) expression in various organs has been linked with several autoimmune diseases. Monoclonal antibodies specific for alpha4 integrins or their CAM ligands can moderate inflammation in animal models suggesting such inhibitors may be useful for treating human inflammatory diseases. The alpha4 integrins have become well validated drug targets for pharmaceutical companies and numerous publications describing alpha4 integrin antagonists have recently appeared. This article discusses the rationale for targeting alpha4 integrins for the treatment of autoimmune disorders and reviews some currently known antagonists. The methods used to identify lead molecules and the progress of selected antagonists toward becoming new drugs will is also discussed. (131 references).
Jackson
David Y
DY
Department of Bioorganic Chemistry, Genentech Inc., 1 DNAWay, MS18, Francisco, CA 94080, USA. davej@gene.com
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000378:metabolism*; D015815:Cell Adhesion Molecules; D002634:Chemotaxis, Leukocyte / Q000187:drug effects*; D006801:Humans; D007136:Immunoglobulins / Q000096:biosynthesis; D039041:Integrin alpha4beta1; D016023:Integrins / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D009088:Mucoproteins / Q000096:biosynthesis; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology; D019151:Peptide Library; D016201:Receptors, Lymphocyte Homing / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis
D000911:Antibodies, Monoclonal; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D039041:Integrin alpha4beta1; D016023:Integrins; C504265:MADCAM1 protein, human; D009088:Mucoproteins; D009842:Oligopeptides; D019151:Peptide Library; D016201:Receptors, Lymphocyte Homing; D019010:Vascular Cell Adhesion Molecule-1; C071777:integrin alpha4beta7