Structure-guided design of pure orthosteric inhibitors of αIIbβ3 that prevent thrombosis but preserve hemostasis

Adair, Brian D.; Alonso, José L.; van Agthoven, Johannes; Hayes, Vincent; Ahn, Hyun Sook; Yu, I-Shing; Lin, Shu-Wha; Xiong, Jian-Ping; Poncz, Mortimer; Arnaout, M. Amin

doi:10.1038/s41467-019-13928-2

Title: Structure-guided design of pure orthosteric inhibitors of αIIbβ3 that prevent thrombosis but preserve hemostasis

Journal Article · 20 January 2020 · Nature Communications

DOI: https://doi.org/10.1038/s41467-019-13928-2 · OSTI ID:1838536

Adair, Brian D. ^[1]; Alonso, José L. ^[1]; van Agthoven, Johannes ^[1]; Hayes, Vincent ^[2]; Ahn, Hyun Sook ^[2];

^[3]; Lin, Shu-Wha ^[4]; Xiong, Jian-Ping ^[1]; Poncz, Mortimer ^[2];

^[1]

Massachusetts General Hospital, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
The Children's Hospital of Philadelphia, PA (United States)
National Taiwan Univ., Taipei (Taiwan). Lab. Animal Center
National Taiwan Univ., Taipei (Taiwan)

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.

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Research Organization:: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: National Institutes of Health (NIH); USDOE Office of Science (SC)

OSTI ID:: 1838536

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 11; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Delayed targeting of CD39 to activated platelet GPIIb/IIIa via a single-chain antibody: breaking the link between antithrombotic potency and bleeding? Hohmann, Jan David; Wang, Xiaowei; Krajewski, Stefanie Blood, Vol. 121, Issue 16 https://doi.org/10.1182/blood-2012-08-449694	journal	April 2013
Full activation of mouse platelets requires ADP secretion regulated by SERCA3 ATPase–dependent calcium stores Elaïb, Ziane; Adam, Frédéric; Berrou, Eliane Blood, Vol. 128, Issue 8 https://doi.org/10.1182/blood-2015-10-678383	journal	August 2016
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Spreading of platelets on fibrin is mediated by the amino terminus of the beta chain including peptide beta 15-42 Hamaguchi, M.; Bunce, La; Sporn, La Blood, Vol. 81, Issue 9 https://doi.org/10.1182/blood.V81.9.2348.2348	journal	May 1993
Acute thrombocytopenia after treatment with tirofiban or eptifibatide is associated with antibodies specific for ligand-occupied GPIIb/IIIa Bougie, Daniel W.; Wilker, Peter R.; Wuitschick, Elizabeth D. Blood, Vol. 100, Issue 6 https://doi.org/10.1182/blood.v100.6.2071.h81802002071_2071_2076	journal	September 2002
Spreading of platelets on fibrin is mediated by the amino terminus of the beta chain including peptide beta 15-42 Hamaguchi, M.; Bunce, La; Sporn, La Blood, Vol. 81, Issue 9 https://doi.org/10.1182/blood.v81.9.2348.bloodjournal8192348	journal	May 1993
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High Affinity vs. Native Fibronectin in the Modulation of αvβ3 Integrin Conformational Dynamics: Insights from Computational Analyses and Implications for Molecular Design Paladino, Antonella; Civera, Monica; Belvisi, Laura PLOS Computational Biology, Vol. 13, Issue 1 https://doi.org/10.1371/journal.pcbi.1005334	journal	January 2017
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Hemodialysis access thrombosis Quencer, Keith Bertram; Oklu, Rahmi Cardiovascular Diagnosis and Therapy, Vol. 7, Issue S3 https://doi.org/10.21037/cdt.2017.09.08	journal	December 2017
Function and Antagonism of β Integrins in the Development of Cancer Therapy Sheldrake, H.; Patterson, L. Current Cancer Drug Targets, Vol. 9, Issue 4 https://doi.org/10.2174/156800909788486713	journal	June 2009
Platelet Integrins in Tumor Metastasis: Do They Represent a Therapeutic Target? Lavergne, Marion; Janus-Bell, Emily; Schaff, Mathieu Cancers, Vol. 9, Issue 10 https://doi.org/10.3390/cancers9100133	journal	September 2017

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