Wang Aili, Wang Tianyu, Chen Haidong, Fang Siwen, Chen Xue, Xu Gaochi, Chen Zhiyun, Liu Ming, Shen Chuanbin, Lai Ren
Center for Evolution and Conservation Biology, Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, China.
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Thromb Haemost. 2026 Mar 3. doi: 10.1055/a-2815-5095.
Thrombosis is the key driver for ischemic events, including stroke, which is the leading cause of global mortality. However, current antithrombotic therapies carry substantial bleeding risks. Targeting protease-activated receptor-1 (PAR-1), a thrombin-activated receptor central to thrombus growth, represents a promising antithrombotic strategy for safer intervention.we mined the venom gland transcriptome of Conus spp., applied in silico Furin cleavage prediction, and synthesized and screened the anti-PAR-1 activity of a series of conotoxin-derived peptides.Cb-26 exhibited the strongest but reversible activity in inhibiting PAR-1-mediated platelet activation and aggregation in vitro. Crucially, Cb-26 inhibited platelet adhesion, neutrophil extracellular traps formation, and thrombus growth under shear conditions in whole blood from healthy donors. In murine models, Cb-26 significantly delayed carotid occlusion and reduced cerebral infarct size in photochemical-induced ischemic stroke, without affecting blood coagulation and bleeding time.These results suggest that Cb-26 is a selective and reversible PAR-1 antagonist and represents a promising antithrombotic candidate without apparent bleeding side effects.
血栓形成是包括中风在内的缺血性事件的关键驱动因素，中风是全球死亡的主要原因。然而，目前的抗血栓治疗存在重大出血风险。靶向蛋白酶激活受体-1（PAR-1），一种对血栓生长至关重要的凝血酶激活受体，代表了一种有前景的更安全抗血栓干预策略。我们挖掘了芋螺属动物的毒腺转录组，应用计算机模拟弗林蛋白酶切割预测，并合成和筛选了一系列芋螺毒素衍生肽的抗PAR-1活性。Cb-26在体外抑制PAR-1介导的血小板活化和聚集方面表现出最强但可逆的活性。至关重要的是，Cb-26在来自健康供体的全血剪切条件下抑制血小板粘附、中性粒细胞胞外诱捕网形成和血栓生长。在小鼠模型中，Cb-26显著延迟了光化学诱导的缺血性中风中的颈动脉闭塞并减小了脑梗死面积，而不影响凝血和出血时间。这些结果表明Cb-26是一种选择性和可逆的PAR-1拮抗剂，是一种没有明显出血副作用的有前景的抗血栓候选药物。
