Small-molecule inhibitors of integrin α2β1 that prevent pathological thrombus formation via an allosteric mechanism

Meredith W. Miller, Sandeep Basra, Daniel W. Kulp, Paul C. Billings, Sungwook Choi, Mary Pat Beavers, Owen McCarty, Zhiying Zou, Mark L. Kahn, Joel S. Bennett, William F. DeGrado

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

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 α2β1, 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 α2β1 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 α2β1 could be a potentially safe, effective approach to long-term therapy for cardiovascular disease.

Original languageEnglish (US)
Pages (from-to)719-724
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number3
DOIs
StatePublished - Jan 20 2009

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Integrins
Thrombosis
Blood Platelets
Collagen Receptors
Hemostasis
Vascular Diseases
Cardiovascular Diseases
Animal Models
Stroke
Myocardial Infarction
Hemorrhage
Therapeutics

Keywords

  • Alpha(2) beta(1)
  • I-domain
  • Integrin
  • Platelet
  • Thrombosis

ASJC Scopus subject areas

  • General

Cite this

Small-molecule inhibitors of integrin α2β1 that prevent pathological thrombus formation via an allosteric mechanism. / Miller, Meredith W.; Basra, Sandeep; Kulp, Daniel W.; Billings, Paul C.; Choi, Sungwook; Beavers, Mary Pat; McCarty, Owen; Zou, Zhiying; Kahn, Mark L.; Bennett, Joel S.; DeGrado, William F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 3, 20.01.2009, p. 719-724.

Research output: Contribution to journalArticle

Miller, Meredith W. ; Basra, Sandeep ; Kulp, Daniel W. ; Billings, Paul C. ; Choi, Sungwook ; Beavers, Mary Pat ; McCarty, Owen ; Zou, Zhiying ; Kahn, Mark L. ; Bennett, Joel S. ; DeGrado, William F. / Small-molecule inhibitors of integrin α2β1 that prevent pathological thrombus formation via an allosteric mechanism. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 3. pp. 719-724.
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