血小板中的 PROTACs:新出现的抗血栓策略和未来展望。

IF 3.1 3区 医学 Q2 HEMATOLOGY
Current Opinion in Hematology Pub Date : 2025-01-01 Epub Date: 2024-10-18 DOI:10.1097/MOH.0000000000000846
Justin S Trory, Jordan Vautrinot, Carl J May, Ingeborg Hers
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引用次数: 0

摘要

综述目的:蛋白质分解靶向嵌合体(PROTACs)是一种选择性靶向降解蛋白质的异功能化合物,是治疗癌症和神经退行性疾病等疾病的一种新兴疗法。本综述将拓宽其应用领域,重点介绍 PROTACs 从无核血小板中去除蛋白质的能力,并评估其抗血栓形成的潜力:蛋白质组学和生物化学研究表明,人类血小板具有泛素蛋白酶体系统和 E3 连接酶 cereblon (CRBN),因此可能易受 PROTAC 介导的蛋白质降解作用的影响。最近的研究结果证实,基于 CRBN 配体的 PROTACs 以一般酪氨酸激酶、Btk 和/或 Fak 为靶点,能有效地选择性降解人血小板中的蛋白质。Btk 是参与血栓形成信号传导的关键因子,但不参与止血,Btk 的下调导致体外血栓形成受损。因此,PROTACs 是研究血小板功能的又一研究工具,并为预防血栓形成提供了新的治疗潜力。未来的研究应侧重于增强细胞特异性,以避免对其他血细胞产生靶向副作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
PROTACs in platelets: emerging antithrombotic strategies and future perspectives.

Purpose of review: Proteolysis-targeted chimeras (PROTACs) are heterobifunctional compounds that selectively target proteins for degradation and are an emerging therapeutic modality to treat diseases such as cancer and neurodegenerative disorders. This review will widen the area of application by highlighting the ability of PROTACs to remove proteins from the anucleate platelets and evaluate their antithrombotic potential.

Recent findings: Proteomic and biochemical studies demonstrated that human platelets possess the Ubiquitin Proteasomal System as well as the E3 ligase cereblon (CRBN) and therefore may be susceptible to PROTAC-mediated protein degradation. Recent findings confirmed that CRBN ligand-based PROTACs targeting generic tyrosine kinases, Btk and/or Fak lead to efficacious and selective protein degradation in human platelets. Downregulation of Btk, a key player involved in signalling to thrombosis, but not haemostasis, resulted in impaired in-vitro thrombus formation.

Summary: Platelets are susceptible to targeted protein degradation by CRBN ligand-based PROTACs and have limited ability to resynthesise proteins, ensuring long-term downregulation of target proteins. Therefore, PROTACs serve as an additional research tool to study platelet function and offer new therapeutic potential to prevent thrombosis. Future studies should focus on enhancing cell specificity to avoid on-target side effects on other blood cells.

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来源期刊
CiteScore
6.60
自引率
3.10%
发文量
78
审稿时长
6-12 weeks
期刊介绍: ​​​​​​​​Current Opinion in Hematology is an easy-to-digest bimonthly journal covering the most interesting and important advances in the field of hematology. Its hand-picked selection of editors ensure the highest quality selection of unbiased review articles on themes from nine key subject areas, including myeloid biology, Vascular biology, hematopoiesis and erythroid system and its diseases.
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