Examining targeted protein degradation from physiological and analytical perspectives: Enabling translation between cells and subjects.,ACS Chemical Biology

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Examining targeted protein degradation from physiological and analytical perspectives: Enabling translation between cells and subjects.
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2020-09-15 , DOI: 10.1021/acschembio.0c00380
Natalie A Daurio ₁ , Haihong Zhou ₁ , Ying Chen ₁ , Payal R Sheth ₁ , Jason E Imbriglio ₁ , David G McLaren ₁ , Paul Tawa ₁ , Nadia Rachdaoui ₂ , Michael J Previs ₃ , Takhar Kasumov ₄ , Jennifer O'Neil ₁ , Stephen F Previs ₁

Affiliation

The ability to target specific proteins for degradation may open a new door toward developing therapeutics. Although effort in chemistry is essential for advancing this modality, i.e., one needs to generate proteolysis targeting chimeras (bifunctional molecules, also referred to as PROTACS) or “molecular glues” to accelerate protein degradation, we suspect that investigations could also benefit by directing attention toward physiological regulation surrounding protein homeostasis, including the methods that can be used to examine changes in protein kinetics. This perspective will first consider some metabolic scenarios that might be of importance when one aims to change protein abundance by increasing protein degradation. Specifically, could protein turnover impact the apparent outcome? We will then outline how to study protein dynamics by coupling stable isotope tracer methods with mass spectrometry-based detection; since the experimental conditions could have a dramatic effect on protein turnover, special attention is directed toward the application of methods for quantifying protein kinetics using in vitro and in vivo models. Our goal is to present key concepts that should enable mechanistically informed studies which test targeted protein degradation strategies.

中文翻译：

从生理和分析角度检查目标蛋白质的降解：启用细胞和受试者之间的翻译。

靶向降解特定蛋白质的能力可能会为开发治疗药物打开新的大门。尽管化学方面的努力对于推进这种模式至关重要，也就是说，需要产生针对嵌合体（双功能分子，也称为PROTACS）或“分子胶”的蛋白水解以加速蛋白质降解，但我们怀疑，研究也可能会通过吸引注意力而受益围绕蛋白质稳态的生理调节，包括可用于检查蛋白质动力学变化的方法。该观点将首先考虑一些代谢场景，这些场景可能在通过增加蛋白质降解来改变蛋白质丰度时可能很重要。特别，蛋白质更新会否影响表观结果？然后，我们将概述如何通过将稳定的同位素示踪剂方法与基于质谱的检测方法结合来研究蛋白质动力学。由于实验条件可能对蛋白质更新产生巨大影响，因此应特别注意使用蛋白质定量动力学的方法的应用体外和体内模型。我们的目标是提出关键的概念，以使能够进行有机械学识的研究来测试目标蛋白质降解策略。

更新日期：2020-10-17

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