Structure-guided design of a pure orthosteric antagonist of integrin αlIbβ3 that inhibits thrombosis but not clot retraction

Platelet integrin αlIbβ3 plays a critical role in both hemostasis and thrombosis. Current αIIbβ3 antagonists are potent anti-thrombotic drugs, but also cause adverse outcomes, which limited their clinical use. Drug-induced serious bleeding, thrombocytopenia and paradoxical thrombosis have been linked to impaired clot retraction and to conformational changes in αIIbβ3 that promote binding of preformed antibodies, natural ligands or both to αIIbβ3. We have used structure-guided design to generate the orthosteric inhibitor Hr10 that acts as a pure αIIbβ3 antagonist, i.e. it does not induce the conformational changes in αIIbβ3. Hr10 is as effective as the partial agonist drug eptifibatide in blocking platelet aggregation and arteriolar thrombosis in mice. In contrast to eptifibatide, however, Hr10 preserved thrombin-induced clot retraction, suggesting that it may not perturb hemostasis. Our structure-based approach can find general utility in designing pure orthosteric inhibitors for other integrins, in providing vital tools for dissecting structure-activity relationships in αIIbβ3, and potentially in offering safer alternatives for human therapy.