Modeling the Degradation Effects of Autophagosome Tethering Compounds
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LETTER TO THE EDITOR
Modeling the Degradation Effects of Autophagosome Tethering Compounds Hang Zhang1 • Ping An2 • Yiyan Fei1 • Boxun Lu2
Received: 11 April 2020 / Accepted: 14 May 2020 Ó Shanghai Institutes for Biological Sciences, CAS 2020
Dear Editor, 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 Hang Zhang and Ping An contributed equally to this work.
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12264-020-00574-8) contains supplementary material, which is available to authorized users. & Yiyan Fei [email protected] & Boxun Lu [email protected] 1
Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Key Laboratory of Micro and Nano Photonic Structures (Ministry of Education), Fudan University, Shanghai 200433, China
2
State Key Laboratory of Medical Neurobiology and Ministry of Education Frontiers Center for Brain Science, School of Life Sciences, Fudan University, Shanghai 200438, China
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 degra
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