Authors

Discussion

Lysosomal storage disorders (LSDs) are complex metabolic disorders characterised by an abnormal build-up of toxic materials within lysosomes as a result of lysosomal enzyme defects. Due to the complex nature of these disorders, currently, there is no available treatment for the majority of LSDs. Acid ceramidase (ACase), a lipid hydrolase that cleaves ceramide, contributes to the pathology of LSDs by deacylating accumulating glycosphingolipids into lyso-glycosphingolipids, which are potent signalling lipids and are toxic to cells. Therefore, ACase makes a promising therapeutic target as a potential treatment for LSDs.

The cytotoxic chemotherapeutic drug Carmofur is a potent, covalent inhibitor of ACase. However, with the majority of LSD patients being children, Carmofur is unsuitable as a chronic administration treatment for a juvenile population. Additionally, over-inhibition of ACase causes the development of Farber disease, an aggressive LSD. Therefore, our aim is to inhibit ACase enough to alleviate lysosphingolipid-induced pathology, but not enough to induce Farber disease. We aim to do this by developing a non-covalent inhibitor of ACase.

After establishing a fluorescence-based assay to measure ACase activity, we tested numerous in‑house compounds for ACase inhibition. Our most promising compound, compound A, inhibits ACase with an IC₅₀ of 1.4 µM. Preliminary work has also shown that compound A is a non-covalent inhibitor of ACase. Further work, including crystallisation of ACase and compound A, will help discover better inhibitors of ACase.