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药物发现与治疗进展中蛋白质-蛋白质相互作用调节剂的新见解。

New insights into protein-protein interaction modulators in drug discovery and therapeutic advance.

作者信息

Nada Hossam, Choi Yongseok, Kim Sungdo, Jeong Kwon Su, Meanwell Nicholas A, Lee Kyeong

机构信息

BK21 FOUR Team and Integrated Research Institute for Drug Development, College of Pharmacy, Dongguk University-Seoul, Goyang, Republic of Korea.

Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, USA.

出版信息

Signal Transduct Target Ther. 2024 Dec 6;9(1):341. doi: 10.1038/s41392-024-02036-3.

DOI:10.1038/s41392-024-02036-3
PMID:39638817
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11621763/
Abstract

Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered to be undruggable targets have become increasingly feasible due to the progress that has been made over the last two decades and the rapid technological advances. This work explores the influence of technological innovations on PPI research and development. Additionally, the diverse strategies for discovering, modulating, and characterizing PPIs and their corresponding modulators are examined with the aim of presenting a streamlined pipeline for advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in PPI modulator discovery and development, we aim to illustrate the efficacy of various strategies for identifying, optimizing, and overcoming challenges associated with PPI modulator design. The valuable lessons and insights gained from the identification, optimization, and approval of PPI modulators are discussed with the aim of demonstrating that PPI modulators have transitioned beyond early-stage drug discovery and now represent a prime opportunity with significant potential. The selected examples of PPI modulators encompass those developed for cancer, inflammation and immunomodulation, as well as antiviral applications. This perspective aims to establish a foundation for the effective targeting and modulation of PPIs using PPI modulators and pave the way for future drug development.

摘要

蛋白质-蛋白质相互作用（PPIs）是细胞信号传导和转导的基础，这使其成为有吸引力的治疗药物开发靶点。由于过去二十年取得的进展和快速的技术进步，曾经被认为不可成药的靶点变得越来越可行。这项工作探讨了技术创新对PPI研究与开发的影响。此外，还研究了发现、调节和表征PPIs及其相应调节剂的各种策略，目的是提出一个推进以PPI为靶点的治疗方法的简化流程。通过展示PPI调节剂发现与开发中精心挑选的案例研究，我们旨在说明识别、优化和克服与PPI调节剂设计相关挑战的各种策略的有效性。讨论了从PPI调节剂的识别、优化和批准中获得的宝贵经验教训和见解，目的是证明PPI调节剂已经超越了早期药物发现阶段，现在代表着一个具有巨大潜力的绝佳机会。所选的PPI调节剂示例包括为癌症、炎症和免疫调节以及抗病毒应用而开发的那些。这一观点旨在为使用PPI调节剂有效靶向和调节PPIs奠定基础，并为未来的药物开发铺平道路。

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