Acid ceramidase inhibition as a mechanism to treat lysosomal disorders

Davies, Mari, Riseley, Ross, Jones, Dyfyr H. and Waller-Evans, Helen ORCID: https://orcid.org/0000-0003-4133-6064 2023. Acid ceramidase inhibition as a mechanism to treat lysosomal disorders. Molecular Genetics and Metabolism 138 (2) , 107069. 10.1016/j.ymgme.2022.107069

Full text not available from this repository.

Abstract

Lysosomal disorders (LDs) are complex metabolic disorders characterised by an abnormal build-up of toxic materials within lysosomes as a result of lysosomal enzyme defects. There is no available treatment for the majority of LDs. Acid ceramidase (ACase), a lipid hydrolase that cleaves ceramide, contributes to the pathology of LDs 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 LDs. The cytotoxic chemotherapeutic drug Carmofur is a potent, covalent inhibitor of ACase. However, with the majority of LD 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 LD. Therefore, our aim is to inhibit ACase enough to alleviate lysosphingolipid-induced pathology, but not enough to induce Farber disease; our data indicate that a 50% reduction in ACase activity yields the maximal benefit in several LDs. We aim to do this by developing a non-covalent inhibitor of ACase. We have also measured the effects of ACase inhibition on TFEB activation by high content microscopy to investigate potential additional mechanisms by which ACase inhibition delivers benefit. Our first strategy is to convert existing potent covalent inhibitors to non-covalent. Our most promising compound in this series, 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. Our second strategy was to screen a library of 50,000 compounds, which identified compound B, an ACase inhibitor with an IC50 of 545 nM. We are currently working to improve these molecules, and hope that ongoing efforts to co-crystallise ACase with our compounds will help discover better inhibitors of ACase.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Biosciences
Publisher:	Elsevier
ISSN:	1096-7192
Last Modified:	20 Mar 2023 13:00
URI:	https://orca.cardiff.ac.uk/id/eprint/157790

Actions (repository staff only)

Edit Item