{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T12:04:59Z","timestamp":1765368299924,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T00:00:00Z","timestamp":1746748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council","award":["NSTC 113-2311-B-006-002"],"award-info":[{"award-number":["NSTC 113-2311-B-006-002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Current \u03b1IIb\u03b23 antagonists are potent antithrombotic agents, their clinical use is limited by the risk of life-threatening bleeding. Emerging evidence has highlighted key mechanistic differences between thrombosis and hemostasis, opening avenues for safer antithrombotic strategies. Targeting integrin \u03b1IIb\u03b23 outside-in signaling has been proposed to mitigate bleeding risk; however, the short half-life of peptide-based therapeutics remains a major challenge. In this study, we developed an optimized \u03b1IIb\u03b23 antagonist, KGDRR\u2014a recombinant mutant protein derived from snake venom disintegrin, incorporating an Arg55 residue within the KGD loop\u2014through systematic structure\u2013activity relationship (SAR) analysis. Molecular docking revealed a critical cation\u2013\u03c0 interaction between Arg55 of KGDRR and Tyr122 of the \u03b23 subunit, stabilizing integrin \u03b1IIb\u03b23 in an unliganded-closed conformation. Functionally, KGDRR selectively inhibited thrombus propagation by blocking ligand binding and downstream G\u03b113-mediated outside-in signaling while preserving initial thrombus core formation, which is a limitation of current \u03b1IIb\u03b23 inhibitors. Unlike conventional antagonists, KGDRR maintained \u03b1IIb\u03b23 in an unliganded-closed conformation without inducing the integrin activation and conformational change that lead to immune-mediated platelet clearance and thrombocytopenia. In animal models, KGDRR effectively suppressed thrombus growth without causing thrombocytopenia or prolonging bleeding time. Furthermore, intramuscular administration of KGDRR achieved a functional half-life 3.5 times longer than that of the clinically used antithrombotic eptifibatide at equivalent antithrombotic efficacy. In conclusion, KGDRR exhibits potent antithrombotic activity with a favorable safety profile and enhanced pharmacokinetic stability. These findings position KGDRR as a promising next generation \u03b1IIb\u03b23 antagonist with the potential to improve clinical outcomes in antithrombotic therapy.<\/jats:p>","DOI":"10.3390\/ijms26104530","type":"journal-article","created":{"date-parts":[[2025,5,9]],"date-time":"2025-05-09T06:18:51Z","timestamp":1746771531000},"page":"4530","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Novel KGD-Based \u03b1IIb\u03b23 Antagonist Prevents Arterial Thrombosis While Preserving Hemostasis and Avoiding Thrombocytopenia"],"prefix":"10.3390","volume":"26","author":[{"given":"Yu-Ju","family":"Kuo","sequence":"first","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3096-8974","authenticated-orcid":false,"given":"Ching-Hu","family":"Chung","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4888-3709","authenticated-orcid":false,"given":"Chun-Chao","family":"Chen","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ju-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kuan-Rau","family":"Chiou","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei 23561, Taiwan"},{"name":"Division of Cardiology, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 23561, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8265-3678","authenticated-orcid":false,"given":"Joen-Rong","family":"Sheu","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Woei-Jer","family":"Chuang","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, National Cheng Kung University Medical College, Tainan 701, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tur-Fu","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Mackay Medical College, New Taipei City 252, Taiwan"},{"name":"Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei 100233, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1161\/CIRCRESAHA.112.300570","article-title":"Integrin \u03b1IIb\u03b23: From Discovery to Efficacious Therapeutic Target","volume":"112","author":"Bledzka","year":"2013","journal-title":"Circ. 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