Author: Jackson, D.Y.

Source: Current Drug Metabolism, Volume 8, Number 14, 1 June 2002 , pp. 1229-1253(25)

Publisher: Bentham Science Publishers

Abstract:

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 4 integrins, 41 and 47, 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 4 integrins or their CAM ligands can moderate inflammation in animal models suggesting such inhibitors may be useful for treating human inflammatory diseases. The 4 integrins have become well validated drug targets for pharmaceutical companies and numerous publications describing 4 integrin antagonists have recently appeared. This article discusses the rationale for targeting 4 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).

Keywords: alpha 4 integrin; alpha 4 beta 1 antagonist; vcam; mad cam

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1381612023394737

Publication date: 2002-06-01

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• Current Pharmaceutical Design publishes timely in-depth reviews covering all aspects of current research in rational drug design. Each issue is devoted to a single major therapeutic area. A Guest Editor who is an acknowledged authority in a therapeutic field has solicits for each issue comprehensive and timely reviews from leading researchers in the pharmaceutical industry and academia.
  
  Each thematic issue of Current Pharmaceutical Design covers all subject areas of major importance to modern drug design, including: medicinal chemistry, pharmacology, drug targets and disease mechanism.

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