The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Second Military Medical University (Naval Medical University), Shanghai 200433, P.R. China.
J Med Chem. 2024 Sep 12;67(17):15807-15815. doi: 10.1021/acs.jmedchem.4c01449. Epub 2024 Aug 15.
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.
通过溶酶体途径进行靶向蛋白降解引起了越来越多的关注，并扩展了可降解蛋白的范围。然而，内源性溶酶体降解策略主要基于抗体或纳米体。有效的小分子溶酶体降解剂仍然相当罕见。本文通过将小分子配体与含有穿膜肽 NPGY 基序的溶酶体分选肽融合，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 成功地应用于降解膜和细胞内靶标。特别是，PSMLTAC 策略在膜靶标 PD-L1 和细胞内靶标 PDEδ 的降解效率均高于相应的 PROTAC 降解剂。综上所述，该概念验证为靶向蛋白降解提供了一种便捷有效的策略。
