Asian J Pharm Sci. 2026 Apr;21(2):
101149
Hee-Yeon Kim,
Eun Nam Choi,
Gee Eun Lee,
Sanghwa Yoon,
Su Ran Mun,
Eui Jung Jung,
Minji Kim,
Hyomin Lim,
Yang Jae Kang,
Woo-Jae Park,
Yong Tae Kwon,
Joo-Won Park.
Lysosomal storage diseases (LSDs) are a group of inherited metabolic disorders caused by misfolding of lysosomal proteins and their degradation via endoplasmic reticulum-associated degradation (ERAD). Deficiency in LSD-associated enzymes leads to the accumulation of toxic materials within the lysosome. In macroautophagy (hereafter autophagy), autophagic receptors as represented by p62/SQSTM1/Sequestosome-1 collect and deliver their cargoes to the lysosome. Here, we developed the LYSOTAC (LYSOsome-TArgeting Chimera) technology, which enables lysosomal targeting of LSD-associated enzymes while preserving their enzymatic activities. LYSOTAC employs a bifunctional chimera that simultaneously binds an LSD-associated enzyme via the enzyme-binding ligand (EBL) and p62 via the autophagy-targeting ligand (ATL). Upon binding, p62 undergoes self-polymerization to form cargo-p62 complexes, which are sequestered into autophagosomes and delivered to lysosomes, where the enzymes exhibit maximal activity. Here, LYSOTAC compounds targeting β-glucocerebrosidase (GCase) were designed to restore GCase activity in lysosomes and promote glucosylceramide degradation in Gaucher disease fibroblasts. We suggest that LYSOTAC provides a potential therapeutic strategy for LSDs.
Keywords: Autophagy; Gaucher disease; Lysosomal storage diseases; Lysosomal targeting; N-degron pathway; p62/SQSTM1/Sequestosome-1