靶向蛋白质降解(TPD)提供了前所未有的药物发现策略,但它不能降解非蛋白质致病性生物分子。我们以前已经开发了自噬体靶向化合物(ATTEC)的概念,可以靶向致病蛋白进行自噬降解。由于巨自噬(以下简称自噬)能够降解包括非蛋白质生物分子在内的多种底物,ATTEC还应该能够靶向那些非蛋白质生物分子用于自噬降解。在我们最近的研究中,我们已经使用脂滴(LD)作为示例性靶标证明了这种可能性。LD是储存中性脂质的细胞内结构,可以通过自噬降解。基于ATTEC的概念,与LDs和关键吞噬体和自噬体蛋白LC3结合的化合物可能靶向LDs进行自噬降解。我们通过化学接头将鉴定的LC3结合分子连接到已知的LD结合探针来设计和合成此类化合物。在微摩尔浓度下,这些化合物通过预测的机制通过自噬大幅降低LDs,并挽救了细胞和两个独立的肝脏脂质沉着小鼠模型中与LD相关的表型。我们的概念验证研究证明了ATTEC利用自噬降解非蛋白质生物分子的可能性。
Targeted protein degradation (TPD) provides unprecedented drug discovery strategies, but it is incapable of degrading non-protein pathogenic biomolecules. We have previously developed the concept of autophagosome-targeting compounds (
ATTEC), which can target pathogenic proteins to autophagic degradation. Since macroautophagy (autophagy hereafter) is capable of degrading a wide spectrum of substrates including non-protein biomolecules,
ATTEC should also be capable of targeting those non-protein biomolecules for autophagic degradation. Here in our most recent study, we have demonstrated this possibility using lipid droplets (LDs) as an exemplar target. LDs are intracellular structures storing neutral lipids, which can be degraded by autophagy. Based on the concept of
ATTEC, compounds binding with both the LDs and the key phagophore and autophagosome protein LC3 may target LDs to autophagic degradation. We designed and synthesized such compounds by connecting the identified LC3-binding molecules to known LD-binding probes via a chemical linker. At micromolar concentrations, these compounds drastically reduced LDs via autophagy through the predicted mechanism, and rescued LD-related phenotypes in cells and in two independent mouse models with hepatic lipidosis. Our proof-of-concept study demonstrates the possibility of harnessing autophagy to degrade non-protein biomolecules by
ATTEC.