Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds

Li, Zhaoyang; Wang, Cen; Wang, Ziying; Zhu, Chenggang; Li, Jie; Tian, Sha; Ma, Lixiang; Gao, Chao; Yang, Yi; Sun, Yi‐Min; Wang, Jian; Sun, Xiaoli; Lu, Chenqi; DiFiglia, Marian; Mei, Yan‐Ai; Chen, Ding; Luo, Shouqing; Dang, Yongjun; Ding, Yu; Fei, Yiyan; Lu, Boxun

doi:10.1038/s41586-019-1722-1

Cited by 342 publications

(359 citation statements)

References 40 publications

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“…We demonstrated that compounds that interact with both the POI and the autophagosome protein LC3 may tether POI to autophagosomes for subsequent autophagic degradation [3] . Since ATTEC tether POI directly to the PDM without involvement of complicated enzymatic reactions, it may provide an ideal scenario for mathematic modeling of the degrader's effects [3] . Here we describe a simplified model of the degradation effects of ATTEC, providing possible insights for understanding the dosedependent data and potential clues for inventing better compounds.…”

Section: Introductionmentioning

confidence: 93%

“…Interestingly, the dose-dependent curves of the POI-compound relationship are Ushaped, with an optimal compound concentration for maximum lowering of POI and "hook" effects at higher compound concentrations [1,3,4] , different from traditional Boltzmann dose-dependent curves [5] . This is explained by the logic reasoning that when the compound concentration is too high, each compound molecule may interact with the POI and PDM separately, without tethering them together.…”

Section: Introductionmentioning

confidence: 95%

“…Selectively degradation of specific pathogenic proteins provides exciting strategies for drug discovery. Emerging new concepts such as PROTAC, ENDTAC, ATTEC are based on the design of "molecular glues" or bifunctional chimeric compounds that tether the target protein (protein of interest, POI) with a certain component of the protein degradation machinery (PDM) [1][2][3] . The formed trimer (POIcompoundPDM) then accelerates the POI degradation, leading its selective lowering.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…We have proposed and demonstrated a new degrader technology by harnessing autophagy for selective degradation using autophagosome tethering compounds (ATTEC) [3] . We demonstrated that compounds that interact with both the POI and the autophagosome protein LC3 may tether POI to autophagosomes for subsequent autophagic degradation [3] . Since ATTEC tether POI directly to the PDM without involvement of complicated enzymatic reactions, it may provide an ideal scenario for mathematic modeling of the degrader's effects [3] .…”

Section: Introductionmentioning

confidence: 99%

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Modeling the Degradation Effects of Autophagosome Tethering Compounds (ATTEC)

zhang

Fei

et al. 2020

Preprint

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Autophagy is a powerful protein degradation pathway with limited specificity. Our recent study proposed and demonstrated a potential strategy to harness autophagy to selectively degrade a specific pathogenic protein using autophagosome tethering compounds (ATTEC). ATTEC interact with both the target protein and the autophagosome protein LC3, and thus tether the target protein to the autophagosomes for subsequent degradation.The concentration-dependent curve of the target protein is U-shaped, but there has been lack of both kinetic and steady-state modeling of the degradation effects of ATTEC. Here we established a simplified model describing the kinetics and steady-state level of target protein, and characterized how compounds' properties, especially binding affinities to LC3 and to the target protein, may influence their degradation effects.

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Section: Introductionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Modeling the Degradation Effects of Autophagosome Tethering Compounds (ATTEC)

zhang

Fei

et al. 2020

Preprint

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Genetic manipulation and targeted protein degradation in mammalian systems: practical considerations, tips and tricks for discovery research

Giandomenico

Schuman

2023

FEBS Open Bio

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Gaining a mechanistic understanding of the molecular pathways underpinning cellular and organismal physiology invariably relies on the perturbation of an experimental system to infer causality. This can be achieved either by genetic manipulation or by pharmacological treatment. Generally, the former approach is applicable to a wider range of targets, is more precise, and can address more nuanced functional aspects. Despite such apparent advantages, genetic manipulation (i.e., knock‐down, knock‐out, mutation, and tagging) in mammalian systems can be challenging due to problems with delivery, low rates of homologous recombination, and epigenetic silencing. The advent of CRISPR‐Cas9 in combination with the development of robust differentiation protocols that can efficiently generate a variety of different cell types in vitro has accelerated our ability to probe gene function in a more physiological setting. Often, the main obstacle in this path of enquiry is to achieve the desired genetic modification. In this short review, we will focus on gene perturbation in mammalian cells and how editing and differentiation of pluripotent stem cells can complement more traditional approaches. Additionally, we introduce novel targeted protein degradation approaches as an alternative to DNA/RNA‐based manipulation. Our aim is to present a broad overview of recent approaches and in vitro systems to study mammalian cell biology. Due to space limitations, we limit ourselves to providing the inexperienced reader with a conceptual framework on how to use these tools, and for more in‐depth information, we will provide specific references throughout.

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Understanding, Targeting, and Hijacking Autophagy

Xia

Zhou

et al. 2022

Protein Homeostasis in Drug Discovery

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Allele-selective lowering of mutant HTT protein by HTT–LC3 linker compounds

Cited by 342 publications

References 40 publications

Modeling the Degradation Effects of Autophagosome Tethering Compounds (ATTEC)

Modeling the Degradation Effects of Autophagosome Tethering Compounds (ATTEC)

Genetic manipulation and targeted protein degradation in mammalian systems: practical considerations, tips and tricks for discovery research

Understanding, Targeting, and Hijacking Autophagy

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