Structure-guided design of pure orthosteric inhibitors of ?IIb?3 that prevent thrombosis but preserve hemostasis [electronic resource]

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Tác giả:

Ngôn ngữ: eng

Ký hiệu phân loại: 614.1 Forensic medicine

Thông tin xuất bản: Washington, D.C. : Oak Ridge, Tenn. : United States. Dept. of Energy. Office of Science ; Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy, 2020

Mô tả vật lý: Size: Article No. 398 : , digital, PDF file.

Bộ sưu tập: Metadata

ID: 259913

A prevailing dogma is that inhibition of vascular thrombosis by antagonizing platelet integrin ?IIb?3 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 ?IIb?3 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 ?IIb?3, i.e., they no longer induce the conformational changes in ?IIb?3. 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 ?IIb?3 may thus provide safer alternatives for human therapy, and valuable tools to probe structure?activity relationships in integrins.
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