Characteristic roadmap of linker governs the rational design of PROTACs

IF 14.7 1区医学 Q1 PHARMACOLOGY & PHARMACY

Acta Pharmaceutica Sinica. B Pub Date : 2024-10-01 DOI:10.1016/j.apsb.2024.04.007

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Abstract

Proteolysis targeting chimera (PROTAC) technology represents a groundbreaking development in drug discovery, leveraging the ubiquitin‒proteasome system to specifically degrade proteins responsible for the disease. PROTAC is characterized by its unique heterobifunctional structure, which comprises two functional domains connected by a linker. The linker plays a pivotal role in determining PROTAC's biodegradative efficacy. Advanced and rationally designed functional linkers for PROTAC are under development. Nonetheless, the correlation between linker characteristics and PROTAC efficacy remains under-investigated. Consequently, this study will present a multidisciplinary analysis of PROTAC linkers and their impact on efficacy, thereby guiding the rational design of linkers. We will primarily discuss the structural types and characteristics of PROTAC linkers, and the optimization strategies used for their rational design. Furthermore, we will discuss how factors like linker length, group type, flexibility, and linkage site affect the biodegradation efficiency of PROTACs. We believe that this work will contribute towards the advancement of rational linker design in the PROTAC research area.

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链接器的特征路线图指导着 PROTAC 的合理设计

蛋白水解靶向嵌合体（PROTAC）技术是药物发现领域的一项突破性进展，它利用泛素-蛋白酶体系统特异性地降解导致疾病的蛋白质。PROTAC 的特点是其独特的异功能结构，包括由连接体连接的两个功能域。连接体在决定 PROTAC 的生物降解功效方面起着关键作用。目前正在为 PROTAC 开发设计先进合理的功能连接体。然而，连接体特性与 PROTAC 功效之间的相关性仍未得到充分研究。因此，本研究将对 PROTAC 连接物及其对药效的影响进行多学科分析，从而指导连接物的合理设计。我们将主要讨论 PROTAC 连接体的结构类型和特点，以及用于合理设计的优化策略。此外，我们还将讨论连接体长度、基团类型、灵活性和连接部位等因素如何影响 PROTAC 的生物降解效率。我们相信，这项工作将有助于推动 PROTAC 研究领域的合理连接体设计。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Acta Pharmaceutica Sinica. B Pharmacology, Toxicology and Pharmaceutics-General Pharmacology, Toxicology and Pharmaceutics

CiteScore

22.40

自引率

5.50%

发文量

1051

审稿时长

19 weeks

期刊介绍： The Journal of the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association oversees the peer review process for Acta Pharmaceutica Sinica. B (APSB). Published monthly in English, APSB is dedicated to disseminating significant original research articles, rapid communications, and high-quality reviews that highlight recent advances across various pharmaceutical sciences domains. These encompass pharmacology, pharmaceutics, medicinal chemistry, natural products, pharmacognosy, pharmaceutical analysis, and pharmacokinetics. A part of the Acta Pharmaceutica Sinica series, established in 1953 and indexed in prominent databases like Chemical Abstracts, Index Medicus, SciFinder Scholar, Biological Abstracts, International Pharmaceutical Abstracts, Cambridge Scientific Abstracts, and Current Bibliography on Science and Technology, APSB is sponsored by the Institute of Materia Medica, Chinese Academy of Medical Sciences, and the Chinese Pharmaceutical Association. Its production and hosting are facilitated by Elsevier B.V. This collaborative effort ensures APSB's commitment to delivering valuable contributions to the pharmaceutical sciences community.