Modeling the Degradation Effects of Autophagosome Tethering Compounds.
Modeling the Degradation Effects of Autophagosome Tethering Compounds.
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模拟自噬体束缚化合物的降解效应。
DOI：
10.1007/s12264-020-00574-8
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Lu Boxun
中科院分区：
文献类型：
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作者：
Zhang Hang;An Ping;Fei Yiyan;Lu Boxun
特异性致病蛋白的选择性降解为药物发现提供了令人兴奋的策略。新兴的新概念，如蛋白水解靶向嵌合体和自噬体栓系化合物（ATTEC）是基于“分子胶”或双功能嵌合化合物的设计，其将靶蛋白（感兴趣的蛋白质，POI）栓系到蛋白降解机制（PDM）的特定组分[1-3]。形成的三聚体（POI-化合物-PDM）然后加速POI的降解，导致其选择性还原。有趣的是，POI-化合物关系的剂量依赖性曲线是U形的，具有最佳化合物浓度以最大限度地降低POI，并且在较高的化合物浓度下具有“钩状”效应[1]，不同于传统的玻尔兹曼剂量依赖性曲线[4]。这可以通过以下逻辑来解释：当化合物浓度太高时，每个分子可以分别与POI和PDM相互作用，而不会将它们拴在一起。与此同时，一直缺乏数学模型来描述这种影响。虽然三聚体形成的建模已在顶级期刊上发表[5]，但根本没有考虑POI的降解。这种建模一直是具有挑战性的，因为纳入退化大大增加了建模计算。此外，大多数现有的降解技术都是基于泛素化[1]，这是一种复杂的酶促反应，对模型具有高度挑战性[6]。我们提出并证明了一种新的降解技术，通过利用自噬进行选择性降解，使用ATTECs [2]。我们证明了与POI和自噬体蛋白LC 3相互作用的化合物将POI拴系到自噬体，用于随后的自噬降解[2]。由于ATTEC将POI直接连接到PDM而不涉及复杂的酶反应，因此它们可以为降解剂效应的数学建模提供理想的场景[2]。在这里，我们描述了一个简化的模型的ATTEC的降解效果，为理解剂量依赖性数据和潜在的线索，发明更好的化合物提供可能的见解。许多参数可能会影响降解动力学和剂量依赖性效应[7，8]，将所有参数视为变量可能会使模型高度复杂且难以求解。因此，我们关注POI的降解与ATTEC对POI或LC 3的亲和力之间的关系，并将它们视为唯一的变量。同时，我们估计了所有其他参数的值，并将其视为常数，以尽可能简化模型。基于这些假设，我们根据
The selective degradation of specific pathogenic proteins provides exciting strategies for drug discovery. Emerging new concepts such as proteolysis-targeting chimeras and autophagosome-tethering compounds (ATTECs) are based on the design of ‘‘molecular glues’’or bifunctional chimeric compounds that tether the target protein (protein of interest, POI) to a specific component of the proteindegradation machinery (PDM)[1–3]. The formed trimer (POI–compound–PDM) then accelerates degradation of the POI, leading its selective reduction. Interestingly, the dosedependence curves of the POI-compound relationship are U-shaped, with an optimal compound concentration for maximum lowering of the POI and ‘‘hook’’effects at higher compound concentrations [1], different from traditional Boltzmann dose-dependent curves [4]. This is explained by the logic that when the compound concentration is too high, each molecule may interact with the POI and PDM separately, without tethering them together. Meanwhile, there has been a lack of mathematic modeling describing such effects. While modeling of the trimer formation has been published in a top-tier journal [5], the degradation of the POI was not considered at all. Such modeling has been challenging, because incorporating the degradation greatly increases the modeling calculation. In addition, most of the existing degrader technologies are based on ubiquitination [1], which is a complicated enzymatic reaction that is highly challenging to model [6].We have proposed and demonstrated a new degrader technology by harnessing autophagy for selective degradation using ATTECs [2]. We demonstrated that compounds that interact with both the POI and the autophagosome protein LC3 tether POI to autophagosomes for subsequent autophagic degradation [2]. Since ATTECs tether POI directly to the PDM without involving complicated enzymatic reactions, they may provide an ideal scenario for mathematical modeling of the degrader’s effects [2]. Here, we describe a simplified model of the degradation effects of an ATTEC, providing possible insights for understanding the dose-dependence data and potential clues for inventing better compounds. Many parameters may influence the degradation kinetics and the dose-dependence effects [7, 8], and considering all of them as variables may make the model highly complicated and difficult to resolve. Thus, we focused on the relationship between the degradation of the POI and the ATTEC’s affinity to the POI or LC3, and considered them as the only variables. Meanwhile, we estimated the values of all other parameters and considered them as constants to simplify the model as much as possible. Based on these assumptions, we performed the modeling based on the