A prevailing dogma is that inhibition of vascular thrombosis by antagonizing platelet integrin αIIbβ3 cannot be achieved without compromising hemostasis, thus causing serious bleeding and increased morbidity and mortality. It is speculated that these adverse outcomes result from drug-induced activating conformational changes in αIIbβ3 but direct proof is lacking. Here, we report the structure-guided design of peptide Hr10 and a modified form of the partial agonist drug tirofiban that act as "pure" antagonists of αIIbβ3, i.e., they no longer induce the conformational changes in αIIbβ3. Both agents inhibit human platelet aggregation but preserve clot retraction. Hr10 and modified tirofiban are as effective as partial agonist drugs in inhibiting vascular thrombosis in humanized mice, but neither causes serious bleeding, establishing a causal link between partial agonism and impaired hemostasis. Pure orthosteric inhibitors of αIIbβ3 may thus provide safer alternatives for human therapy, and valuable tools to probe structure-activity relationships in integrins.

中文翻译：

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αIIbβ3 纯正构抑制剂的结构导向设计，可防止血栓形成但保持止血。

一个流行的教条是，在不损害止血的情况下，不能通过拮抗血小板整合素 αIIbβ3 来抑制血管血栓形成，从而导致严重出血并增加发病率和死亡率。据推测，这些不良后果是由药物诱导的 αIIbβ3 构象变化引起的，但缺乏直接证据。在这里，我们报告了肽 Hr10 的结构导向设计和部分激动剂药物替罗非班的修饰形式，它们作为 αIIbβ3 的“纯”拮抗剂，即它们不再诱导 αIIbβ3 的构象变化。两种药物均抑制人血小板聚集，但保持凝块回缩。hr10和改良替罗非班在抑制人源化小鼠血管血栓形成方面与部分激动剂药物一样有效，但均不会引起严重出血，建立部分激动和止血受损之间的因果关系。因此，αIIbβ3 的纯正构抑制剂可为人类治疗提供更安全的替代方案，并为探索整合素中的结构-活性关系提供有价值的工具。