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

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.

doi:10.1021/acsinfecdis.0c00546

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

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.

Authors

John G.M. Mina

Rebecca L. Charlton

Edubiel Alpizar-Sosa

Douglas O. Escrivani

Christopher Brown

Amjed Alqaisi

Maria Paula G. Borsodi

Claudia P. Figueiredo

Emanuelle V. de Lima

Emily A. Dickie

Dr Wenbin Wei wenbin.wei2@durham.ac.uk
Chief Experimental Officer (Bioinformatics)

Robson Coutinho-Silva

Andy Merritt

Terry K. Smith

Michael P. Barrett

Bartira Rossi-Bergmann

Professor Paul Denny p.w.denny@durham.ac.uk
Professor

Professor Patrick Steel p.g.steel@durham.ac.uk
Professor

Abstract

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.

Citation

Mina, J. G., Charlton, R. L., Alpizar-Sosa, E., Escrivani, D. O., Brown, C., Alqaisi, A., …Steel, P. G. (2021). Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase. ACS Infectious Diseases, 7(1), 47-63. https://doi.org/10.1021/acsinfecdis.0c00546

Journal Article Type	Article
Acceptance Date	Nov 24, 2020
Online Publication Date	Dec 8, 2020
Publication Date	2021
Deposit Date	Dec 10, 2020
Publicly Available Date	Jan 20, 2021
Journal	ACS Infectious Diseases
Publisher	American Chemical Society
Peer Reviewed	Peer Reviewed
Volume	7
Issue	1
Pages	47-63
DOI	https://doi.org/10.1021/acsinfecdis.0c00546

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