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Heparin-induced thrombocytopenia (HIT) is a complication caused by administration of the anticoagulant heparin. Although the number of patients with HIT has drastically increased because of coronavirus disease 2019 (COVID-19), the currently used thrombin inhibitors for HIT therapy do not have antidotes to arrest the severe bleeding that occurs as a side effect; therefore, establishment of safer treatments for HIT patients is imperative. Here, we devised a potent thrombin inhibitor based on bivalent aptamers with a higher safety profile via combination with the antidote. Using an anti-thrombin DNA aptamer M08s-1 as a promising anticoagulant, its homodimer and heterodimer with TBA29 linked by a conformationally flexible linker or a rigid duplex linker were designed. The dimerized M08s-1-based aptamers had about 100-fold increased binding affinity to human and mouse thrombin compared with the monomer counterparts. Administration of these bivalent aptamers into mice revealed that the anticoagulant activity of the dimers significantly surpassed that of an approved drug for HIT treatment, argatroban. Moreover, adding protamine sulfate as an antidote against the most potent bivalent aptamer completely suppressed the anticoagulant activity of the dimer. Emerging potent and neutralizable anticoagulant aptamers will be promising candidates for HIT treatment with a higher safety profile.

権利情報:

• Creative Commons BY Attribution 4.0 International
  

キーワード: aptamer, thrombin , antidote, heparin-induced thrombocytopenia, bivalent aptamer , circular aptamer , TBA29

刊行年月日: 2023-08-02

出版者: Elsevier BV

掲載誌:

• Molecular Therapy - Nucleic Acids (ISSN: 21622531) vol. 33 p. 762-772

研究助成金:

• AMED
• Japan Society for the Promotion of Science
• Iketani Science and Technology Foundation
• Senshin Medical Research Foundation

原稿種別: 出版者版 (Version of record)

MDR DOI:

公開URL: https://doi.org/10.1016/j.omtn.2023.07.038

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更新時刻: 2024-11-21 16:31:02 +0900

MDRでの公開時刻: 2024-11-21 16:31:03 +0900