The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents.
The Potential of Proteolytic Chimeras as Pharmacological Tools and Therapeutic Agents.
复制标题
蛋白水解嵌合体作为药理学工具和治疗剂的潜力。
DOI：
10.3390/molecules25245956
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发表时间：
2020-12-16
期刊：
影响因子：
--
通讯作者：
Crosas B
中科院分区：
文献类型：
--
作者：
Coll-Martínez B;Delgado A;Crosas B
通过可药物分子以高度选择性和高效的方式诱导蛋白质降解被称为靶向蛋白质降解(TPD)。TPD作为一个革命性的概念出现在文献中：一个能够在感兴趣蛋白(POI)和E3泛素连接酶之间产生相互作用的异双功能嵌合体将在POI中诱导一系列事件，包括泛素化、靶向蛋白酶体、蛋白分解和功能沉默，起到一种降解击倒的作用。有了这种程序化的蛋白质降解，有毒和致病的蛋白质可以在潜在有效的低药物剂量下从细胞中被耗尽。在许多研究中对这一假说的原则验证使TPD策略成为开发治疗多种未治疗疾病的新的有吸引力的范例。事实上，自从21世纪初提出了最初的特效物(以嵌合体为靶标的蛋白质分解)以来，TPD领域已经非凡地扩大，发展了创新的化学，并开发了多种降解方法。在这篇文章中，我们回顾了这一高度活跃的学科的突破和最近的新概念。
The induction of protein degradation in a highly selective and efficient way by means of druggable molecules is known as targeted protein degradation (TPD). TPD emerged in the literature as a revolutionary idea: a heterobifunctional chimera with the capacity of creating an interaction between a protein of interest (POI) and a E3 ubiquitin ligase will induce a process of events in the POI, including ubiquitination, targeting to the proteasome, proteolysis and functional silencing, acting as a sort of degradative knockdown. With this programmed protein degradation, toxic and disease-causing proteins could be depleted from cells with potentially effective low drug doses. The proof-of-principle validation of this hypothesis in many studies has made the TPD strategy become a new attractive paradigm for the development of therapies for the treatment of multiple unmet diseases. Indeed, since the initial protacs (Proteolysis targeting chimeras) were posited in the 2000s, the TPD field has expanded extraordinarily, developing innovative chemistry and exploiting multiple degradation approaches. In this article, we review the breakthroughs and recent novel concepts in this highly active discipline.
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影响因子：
14.8
作者：
Bondeson DP;Mares A;Smith IE;Ko E;Campos S;Miah AH;Mulholland KE;Routly N;Buckley DL;Gustafson JL;Zinn N;Grandi P;Shimamura S;Bergamini G;Faelth-Savitski M;Bantscheff M;Cox C;Gordon DA;Willard RR;Flanagan JJ;Casillas LN;Votta BJ;den Besten W;Famm K;Kruidenier L;Carter PS;Harling JD;Churcher I;Crews CM
通讯作者：
Crews CM
影响因子：
4
作者：
Buckley DL;Raina K;Darricarrere N;Hines J;Gustafson JL;Smith IE;Miah AH;Harling JD;Crews CM
通讯作者：
Crews CM
影响因子：
5.5
作者：
Ben-Nissan G;Sharon M
通讯作者：
Sharon M
影响因子：
64.8
作者：
Banik SM;Pedram K;Wisnovsky S;Ahn G;Riley NM;Bertozzi CR
通讯作者：
Bertozzi CR
影响因子：
11.2
作者：
Bakker, ABH;van den Oudenrijn, S;Kiuisbeek, AM
通讯作者：
Kiuisbeek, AM