Antileishmanial chemotherapy through clemastine fumarate mediated inhibition of the Leishmania inositol phosphorylceramide synthase

Mina, J. G.M. et al. (2021) Antileishmanial chemotherapy through clemastine fumarate mediated inhibition of the Leishmania inositol phosphorylceramide synthase. ACS Infectious Diseases, 7(1), pp. 47-63. (doi: 10.1021/acsinfecdis.0c00546) (PMID:33291887) (PMCID:PMC7802075)

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Current chemotherapeutics 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 identifies the over-the-counter antihistamine, clemastine fumarate, as a potential antileishmanial drug candidate. The screening for inhibitors of the sphingolipid synthase (inositol phosphorylceramide synthase, IPCS) afforded, following secondary screening against Leishmania major (Lmj) promastigotes, 16 active compounds. Further refinement through the dose response against LmjIPCS and intramacrophage L. major amastigotes identified clemastine fumarate with good activity and selectivity with respect to the host macrophage. On target engagement was supported by diminished sensitivity in a sphingolipid-deficient L. major mutant (ΔLmjLCB2) and altered phospholipid and sphingolipid profiles upon treatment with clemastine fumarate. The drug also induced an enhanced 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 a mouse model of L. amazonensis infection. Overall, these data validate IPCS as an antileishmanial drug target and indicate that clemastine fumarate is a candidate for repurposing for the treatment of leishmaniasis.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Dickie, Dr Emily and Alpizar Sosa, Edubiel Arturo and Barrett, Professor Michael
Authors: Mina, J. G.M., Charlton, R. L., Alpizar-Sosa, E., Escrivani, D. O., Brown, C., Alqaisi, A., Borsodi, M. P. G., Figueiredo, C. P., de Lima, E. V., Dickie, E. A., Wei, W., Coutinho-Silva, R., Merritt, A., Smith, T. K., Barrett, M. P., Rossi-Bergmann, B., Denny, P. W., and Steel, P. G.
College/School:College of Medical Veterinary and Life Sciences > School of Infection & Immunity
Journal Name:ACS Infectious Diseases
Publisher:American Chemical Society
ISSN (Online):2373-8227
Published Online:08 December 2020
Copyright Holders:Copyright © 2020 American Chemical Society
First Published:First published in ACS Infectious Diseases 7(1): 47-63
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
170547The Wellcome Centre for Molecular Parasitology ( Core Support )Andrew WatersWellcome Trust (WELLCOTR)104111/Z/14/ZIII - Parasitology