Small-molecule inhibitors of integrin alpha2beta1 that prevent pathological thrombus formation via an allosteric mechanism.

Journal Article (Journal Article)

There is a grave need for safer antiplatelet therapeutics to prevent heart attack and stroke. Agents targeting the interaction of platelets with the diseased vessel wall could impact vascular disease with minimal effects on normal hemostasis. We targeted integrin alpha(2)beta(1), a collagen receptor, because its overexpression is associated with pathological clot formation whereas its absence does not cause severe bleeding. Structure-activity studies led to highly potent and selective small-molecule inhibitors. Responses of integrin alpha(2)beta(1) mutants to these compounds are consistent with a computational model of their mode of inhibition and shed light on the activation mechanism of I-domain-containing integrins. A potent compound was proven efficacious in an animal model of arterial thrombosis, which demonstrates in vivo efficacy for inhibition of this platelet receptor. These results suggest that targeting integrin alpha(2)beta(1) could be a potentially safe, effective approach to long-term therapy for cardiovascular disease.

Full Text

Duke Authors

Cited Authors

  • Miller, MW; Basra, S; Kulp, DW; Billings, PC; Choi, S; Beavers, MP; McCarty, OJT; Zou, Z; Kahn, ML; Bennett, JS; DeGrado, WF

Published Date

  • January 20, 2009

Published In

Volume / Issue

  • 106 / 3

Start / End Page

  • 719 - 724

PubMed ID

  • 19141632

Pubmed Central ID

  • PMC2625282

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.0811622106


  • eng

Conference Location

  • United States