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发现TRIM58的干,一种新的选择性组织E3酶

Klemens Hoegenauer¹, Shaojian An², Jake Axford³

¹Global Discovery Chemistry, Novartis Institutes for BioMedical Research, Novartis Campus, CH-4002 Basel, Switzerland.

ACS medicinal chemistry letters

|December 20, 2023

概括

研究人员发现了TRIM58的新干,一种E3酶,扩大了超越CRBN和VHL的向蛋白降解 (TPD) 选项. 这项工作通过识别潜在治疗开发的新型TRIM58结合剂来推进TPD策略.

科学领域:

生物化学生物化学
分子生物学分子生物学
药物发现药物发现药物发现

背景情况:

向蛋白降解 (TPD) 提供了一种与传统药理学不同的新疗法策略.
目前的TPD方法主要使用E3结合酶CRBN和VHL,限制了可药物标的范围.
对于TPD应用,需要识别和描述新型E3链酶.

研究的目的:

发现针对TRIM58,E3酶的PRY-SPRY域的新型带.
为了描述与TRIM58.8识别的配体的结合相互作用.
为开发针对TRIM58.8的双功能降解剂提供结构洞察力.

主要方法:

差分扫描光测量 (DSF) 屏幕用于连接体识别.
生物物理验证试验.
使用竞争性结合试验的结构-活性关系 (SAR) 研究.
进行X射线晶体学以确定TRIM58和配体TRIM-473.的共同晶体结构.

主要成果:

通过DSF查识别TRIM58连接物TRIM-473.
确定化学类型的基本SAR的建立.
确定TRIM-58与TRIM-473.3结合的X射线共晶结构.
洞察结合模式和降解设计的潜力.

结论:

发现了包括TRIM-473在内的新型TRIM58连接体,扩大了TPD的E3连接酶谱.
结构数据为设计针对蛋白质降解的双功能分子提供了基础.
这项研究有助于推进TPD作为一种治疗方式.

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