Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase.

Content Provider	Europe PMC
Author	Mina, John G.M. Charlton, Rebecca L. Alpizar-Sosa, Edubiel Escrivani, Douglas O. Brown, Christopher Alqaisi, Amjed Borsodi, Maria Paula G. Figueiredo, Claudia P. de Lima, Emanuelle V. Dickie, Emily A. Wei, Wenbin Coutinho-Silva, Robson Merritt, Andy Smith, Terry K. Barrett, Michael P. Rossi-Bergmann, Bartira Denny, Paul W. Steel, Patrick G.
Copyright Year	2020
Abstract	Currentchemotherapeutics for leishmaniasis have multiple deficiencies,and there is a need for new safe, efficacious, and affordable medicines.This study describes a successful drug repurposing approach that identifiesthe over-the-counter antihistamine, clemastine fumarate, as a potentialantileishmanial drug candidate. The screening for inhibitors of thesphingolipid synthase (inositol phosphorylceramide synthase, IPCS)afforded, following secondary screening against Leishmaniamajor (Lmj) promastigotes, 16 active compounds. Further refinementthrough the dose response against LmjIPCS and intramacrophage L. major amastigotes identified clemastine fumaratewith good activity and selectivity with respect to the host macrophage.On target engagement was supported by diminished sensitivity in asphingolipid-deficient L. major mutant (ΔLmjLCB2) and altered phospholipid and sphingolipid profilesupon treatment with clemastine fumarate. The drug also induced anenhanced host cell response to infection indicative of polypharmacology.The activity was sustained across a panel of Old and New World Leishmania species, displaying an in vivo activity equivalent to the currently used drug, glucantime, in amouse model of L. amazonensis infection. Overall,these data validate IPCS as an antileishmanial drug target and indicatethat clemastine fumarate is a candidate for repurposing for the treatmentof leishmaniasis.
Related Links	https://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7802075&blobtype=pdf
Journal	ACS Infectious Diseases [ACS Infect Dis]
Volume Number	7
DOI	10.1021/acsinfecdis.0c00546
PubMed Central reference number	PMC7802075
Issue Number	1
PubMed reference number	33291887
e-ISSN	23738227
Language	English
Publisher	American ChemicalSociety
Publisher Date	2020-12-08
Access Restriction	Open
Rights License	This is an open access article published under a Creative Commons Attribution (CC-BY) License, which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited. © 2020 American ChemicalSociety
Subject Keyword	Leishmania ceramide sphingolipids repurposing IPCS clemastine fumarate
Content Type	Text
Resource Type	Article
Subject	Infectious Diseases