Strategies for the Discovery and Design of Tissue Plasminogen Activators: Insights Into Bioengineering Objectives

IF 4.2 4区医学 Q2 CHEMISTRY, MEDICINAL Drug Development Research Pub Date : 2025-03-13 DOI:10.1002/ddr.70072

Amirhossein Akbarpour Arsanjani, Davood Rabiei Faradonbeh, Ziba Veisi Malekshahi, Bashir Mosayyebi, Babak Negahdari

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Abstract

Tissue plasminogen activators (tPAs) are critical in fibrinolysis and have become central to treating thrombotic disorders, including heart attacks, strokes, and pulmonary embolisms. Despite their efficacy, challenges such as bleeding complications, limited fibrin specificity, and rapid clearance necessitate the discovery of novel tPAs and the engineering of improved variants. This review highlights strategies for the discovery of tPAs from natural sources, including human, bacterial, venom-derived, and bat saliva-derived agents, as well as enzyme engineering approaches that enhance functional characteristics such as half-life, fibrin specificity, resistance to inhibitors, and clot penetration. Furthermore, this review explores alternative therapeutic approaches independent of tPAs, focusing on nonplasminogen activator agents and strategies that target platelets. By addressing current challenges and identifying future opportunities, this review provides a comprehensive perspective on advancing thrombolytic therapies through innovative discovery and design strategies.

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组织纤溶酶原激活剂的发现和设计策略：对生物工程目标的见解

组织纤溶酶原激活剂（tpa）在纤溶中起关键作用，并已成为治疗血栓性疾病（包括心脏病发作、中风和肺栓塞）的核心。尽管其疗效显著，但出血并发症、有限的纤维蛋白特异性和快速清除等挑战需要发现新的tpa和改进变体的工程。这篇综述强调了从天然来源（包括人类、细菌、毒液来源和蝙蝠唾液来源的药物）中发现tpa的策略，以及增强半衰期、纤维蛋白特异性、对抑制剂的抗性和血栓穿透等功能特征的酶工程方法。此外，本综述探讨了不依赖于tpa的替代治疗方法，重点是非纤溶酶原激活剂和靶向血小板的策略。通过解决当前的挑战和确定未来的机遇，本综述为通过创新的发现和设计策略推进溶栓治疗提供了全面的视角。

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来源期刊

Drug Development Research 医学-药学

CiteScore

6.40

自引率

2.60%

发文量

104

审稿时长

6-12 weeks

期刊介绍： Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.