Targeting integrin structure and function in disease.

Initially linked to the pathogenesis of inflammatory and hematologic diseases, integrins have become validated drug targets with the approval of five drugs. Moreover, there are several promising drug candidates in preclinical and clinical stages of development for multiple clinical indications. Integrins are attractive drug targets as their antagonism can block several steps in disease progression or maintenance. Integrin inhibitors can block the proliferation, migration, or tissue localization of inflammatory, angiogenic, and tumor cells, as well as signaling and gene expression contributing to disease. There has been a rapid increase in the elucidation of integrin structure, their allosteric mechanisms of bidirectional signaling, and the structure of complexes with drugs. This information brings greater focus to how integrins support various cellular functions and how they have been and may be targeted to develop novel drugs. Here we review conformational switches, including an internal ligand, which allosterically regulate the transition from low- to high-affinity ligand binding. We address some of the successes, disappointments, and challenges in targeting competitive or allosteric sites to develop therapeutics. We also discuss new opportunities, including a structure-based approach to discover novel drugs to treat inflammatory and other diseases. This approach targets structural relatives of the von Willebrand factor A-domain present in integrins and many functionally diverse proteins.