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

[Image: see text] 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...

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Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Chemical Society 2020
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802075/
https://www.ncbi.nlm.nih.gov/pubmed/33291887
http://dx.doi.org/10.1021/acsinfecdis.0c00546
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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.
author_facet 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.
author_sort Mina, John G. M.
collection PubMed
description [Image: see text] 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.
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spelling pubmed-78020752021-01-13 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. ACS Infect Dis [Image: see text] 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. American Chemical Society 2020-12-08 2021-01-08 /pmc/articles/PMC7802075/ /pubmed/33291887 http://dx.doi.org/10.1021/acsinfecdis.0c00546 Text en © 2020 American Chemical Society This is an open access article published under a Creative Commons Attribution (CC-BY) License (http://pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html) , which permits unrestricted use, distribution and reproduction in any medium, provided the author and source are cited.
spellingShingle 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.
Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase
title Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase
title_full Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase
title_fullStr Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase
title_full_unstemmed Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase
title_short Antileishmanial Chemotherapy through Clemastine Fumarate Mediated Inhibition of the Leishmania Inositol Phosphorylceramide Synthase
title_sort antileishmanial chemotherapy through clemastine fumarate mediated inhibition of the leishmania inositol phosphorylceramide synthase
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7802075/
https://www.ncbi.nlm.nih.gov/pubmed/33291887
http://dx.doi.org/10.1021/acsinfecdis.0c00546
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