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Antileishmanial chemotherapy through clemastine fumarate mediated inhibition of the Leishmania inositol phosphorylceramide synthase
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dc.contributor.author | Mina, John G.M. | |
dc.contributor.author | Charlton, Rebecca L. | |
dc.contributor.author | Alpizar-Sosa, Edubiel | |
dc.contributor.author | Escrivani, Douglas O. | |
dc.contributor.author | Brown, Christopher | |
dc.contributor.author | Alqaisi, Amjed | |
dc.contributor.author | Borsodi, Maria Paula G. | |
dc.contributor.author | Figueiredo, Claudia P. | |
dc.contributor.author | De Lima, Emanuelle V. | |
dc.contributor.author | Dickie, Emily A. | |
dc.contributor.author | Wei, Wenbin | |
dc.contributor.author | Coutinho-Silva, Robson | |
dc.contributor.author | Merritt, Andy | |
dc.contributor.author | Smith, Terry K. | |
dc.contributor.author | Barrett, Michael P. | |
dc.contributor.author | Rossi-Bergmann, Bartira | |
dc.contributor.author | Denny, Paul W. | |
dc.contributor.author | Steel, Patrick G. | |
dc.date.accessioned | 2021-01-25T15:30:05Z | |
dc.date.available | 2021-01-25T15:30:05Z | |
dc.date.issued | 2021-01-08 | |
dc.identifier | 272332843 | |
dc.identifier | e1e57090-5c96-4a96-9b15-7a44fcc18e9c | |
dc.identifier | 85097771478 | |
dc.identifier | 33291887 | |
dc.identifier | 000609249400005 | |
dc.identifier.citation | 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 & Steel , P G 2021 , ' Antileishmanial chemotherapy through clemastine fumarate mediated inhibition of the Leishmania inositol phosphorylceramide synthase ' , ACS Infectious Diseases , vol. 7 , no. 1 , pp. 47-63 . https://doi.org/10.1021/acsinfecdis.0c00546 | en |
dc.identifier.issn | 2373-8227 | |
dc.identifier.uri | https://hdl.handle.net/10023/21321 | |
dc.description | We thank CNPq (PVE Grant: 400894/2014-9 to B.R.-B. and P.G.S.), The Royal Society (The Royal Society International Collaboration Awards for Research Professors 2016: IC160044 to B.R.-B. and P.G.S.), MRC (iCASE studentship for C.B.; Grant MR/M020118/1 to T.K.S.; MRC Confidence in Concept MC-PC-17157), UKRI Grand Challenges Research Fund (“A Global Network for Neglected Tropical Diseases” grant number MR/P027989/1), Wellcome Trust (104111/Z/14/Z “Wellcome Centre for Integrative Parasitology”), and FAPERJ (Grant: E-26/010.002985/2014 to R.C.-S.) for financial support; Glasgow Polyomics for data acquisition; Professor Simon Croft and Dr. Vanessa Yardley for help with the intramacrophage antiamastigote assays. | en |
dc.description.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. | |
dc.format.extent | 17 | |
dc.format.extent | 2719995 | |
dc.language.iso | eng | |
dc.relation.ispartof | ACS Infectious Diseases | en |
dc.subject | Ceramide | en |
dc.subject | Clemastine fumarate | en |
dc.subject | IPCS | en |
dc.subject | Leishmania | en |
dc.subject | Repurposing | en |
dc.subject | Sphingolipids | en |
dc.subject | RA0421 Public health. Hygiene. Preventive Medicine | en |
dc.subject | QD Chemistry | en |
dc.subject | Infectious Diseases | en |
dc.subject | DAS | en |
dc.subject | SDG 3 - Good Health and Well-being | en |
dc.subject.lcc | RA0421 | en |
dc.subject.lcc | QD | en |
dc.title | Antileishmanial chemotherapy through clemastine fumarate mediated inhibition of the Leishmania inositol phosphorylceramide synthase | en |
dc.type | Journal article | en |
dc.contributor.sponsor | Medical Research Council | en |
dc.contributor.institution | University of St Andrews. School of Biology | en |
dc.contributor.institution | University of St Andrews. Biomedical Sciences Research Complex | en |
dc.identifier.doi | 10.1021/acsinfecdis.0c00546 | |
dc.description.status | Peer reviewed | en |
dc.identifier.grantnumber | MR/M020118/1 | en |
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