Targeting lipid droplets for autophagic degradation by ATTEC

Abstract

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.