Peptide-Mediated Small Molecule Lysosome-Targeting Chimeras for Targeted Degradation of Membrane and Intracellular Proteins,Journal of Medicinal Chemistry

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Peptide-Mediated Small Molecule Lysosome-Targeting Chimeras for Targeted Degradation of Membrane and Intracellular Proteins
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-08-15 , DOI: 10.1021/acs.jmedchem.4c01449
Shuqiang Chen ₁ , Wei Wang ₁ , Zhipeng Chen ₁ , Ruyan Li ₁ , Zhe Wu ₁ , Guoqiang Dong ₁ , Chunquan Sheng ₁

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Targeted protein degradation through the lysosomal pathway has attracted increasing attention and expanded the scope of degradable proteins. However, the endogenous lysosomal degradation strategies are mainly based on antibodies or nanobodies. Effective small molecule lysosomal degraders are still rather rare. Herein, a new lysosomal degradation approach, termed peptide-mediated small molecule lysosome-targeting chimeras (PSMLTACs), was developed by the incorporation of small molecule ligands with a lysosome-sorting NPGY motif containing the cell-penetrating peptide. PSMLTACs were successfully applied to degrade both membrane and intracellular targets. In particular, the PSMLTAC strategy demonstrated higher degradation efficiency on membrane target PD-L1 and intracellular target PDEδ than corresponding PROTAC degraders. Taken together, this proof-of-concept provides a convenient and effective strategy for targeted protein degradation.

中文翻译：

肽介导的小分子溶酶体靶向嵌合体用于膜和细胞内蛋白的靶向降解

通过溶酶体途径进行的靶向蛋白质降解引起了越来越多的关注，并扩大了可降解蛋白质的范围。然而，内源性溶酶体降解策略主要基于抗体或纳米抗体。有效的小分子溶酶体降解剂仍然相当罕见。在此，通过将小分子配体与含有细胞穿透肽的溶酶体分选NPGY基序结合，开发了一种新的溶酶体降解方法，称为肽介导的小分子溶酶体靶向嵌合体（PSMLTAC）。 PSMLTAC 已成功应用于降解膜和细胞内靶标。特别是，PSMLTAC 策略对膜靶点 PD-L1 和细胞内靶点 PDEδ 的降解效率比相应的 PROTAC 降解剂更高。总而言之，这一概念验证为靶向蛋白质降解提供了一种方便且有效的策略。

更新日期：2024-08-15

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