Click chemistry in the development of PROTACs

IF 4.2 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ce Yang, Ravi Tripathi and Binghe Wang
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Abstract

Proteolysis-targeting chimeras or PROTACs are hetero-bifunctional molecules designed to mediate the disposal of a target protein via recruitment of the ubiquitination–proteasome degradation machinery. Because of the chimeric nature of such molecules, their synthesis requires a key step of “assembling” whether in the lab or in situ. Furthermore, targeted PROTACs often are hetero-trifunctional and require a second “assembling” step. Click chemistry has the unique advantages of tethering two or more molecular entities of choice under near physiological conditions and therefore has been applied to the development of PROTACs in various ways. This review provides a succinct summary of this field with a critical analysis of various factors that need to be considered for optimal results. Specifically, we examine issues including applications of click chemistry in in situ assembly for improved delivery, conjugation with a targeting group for selectivity, rapid synthesis for linker optimization, and lysosomal degradation of extracellular and membrane-associated proteins. We also examine reaction kinetics issues whenever possible or warranted.

Abstract Image

开发 PROTAC 的点击化学
蛋白水解靶向嵌合体或 PROTACs 是一种异质双功能分子,旨在通过招募泛素化-蛋白酶体降解机制来处理靶蛋白。由于这类分子的嵌合性质,其合成需要一个关键步骤,即在实验室或原位进行 "组装"。此外,靶向 PROTAC 通常具有异种功能,需要第二个 "组装 "步骤。点击化学具有独特的优势,可以在接近生理的条件下拴住两个或多个所选的分子实体,因此已被以各种方式应用于 PROTACs 的开发。本综述简明扼要地总结了这一领域,并对取得最佳结果需要考虑的各种因素进行了批判性分析。具体来说,我们研究的问题包括:应用点击化学进行原位组装以实现imroved递送、与靶向基团共轭以实现选择性、快速合成以优化连接体,以及细胞外蛋白和膜相关蛋白的溶酶体降解。在可能或有保证的情况下,我们还会研究反应动力学问题。
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
CiteScore
6.10
自引率
0.00%
发文量
128
审稿时长
10 weeks
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