Therapeutic antagonists and conformational regulation of integrin function

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Abstract
Members of the integrin family of adhesion molecules are non-covalently-associated α/β heterodimers that mediate cell–cell, cell–extracellular matrix and cell–pathogen interactions by binding to distinct, but often overlapping, combinations of ligands. Dysregulation of integrins is involved in the pathogenesis of many disease states, from autoimmunity and thrombotic vascular diseases to cancer metastasis, and so extensive efforts have been directed towards the discovery and development of integrin antagonists for clinical applications. Integrin antagonists are already well established as therapeutics for cardiovascular disease, and applications in other therapuetic areas, including inflammatory disease, seem extremely promising. Integrin ligand-binding function is tightly linked to molecular conformation. On activation, dramatic rearrangements occur in the overall spatial relationships of integrin domains. Understanding the structural basis of integrin activation in detail is essential for understanding the mechanism of antagonism by therapeutics, as well as for the design of second-generation antagonists with novel mechanisms of action. This review discusses examples of the three different classes of integrin antagonists discovered so far: α/β I-like competitive antagonists, α/β I-like allosteric antagonists and α I allosteric antagonists. These examples were chosen because they illustrate particularly well the mutually beneficial relationship between integrin drug discovery and our understanding of integrin structure and function.