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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.\u00a0major 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.\u00a0major mutant (\u0394LmjLCB2) 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.\u00a0amazonensis 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.<\/jats:p>","DOI":"10.1021\/acsinfecdis.0c00546","type":"journal-article","created":{"date-parts":[[2020,12,9]],"date-time":"2020-12-09T13:58:19Z","timestamp":1607522299000},"page":"47-63","source":"Crossref","is-referenced-by-count":23,"title":["Antileishmanial Chemotherapy through Clemastine Fumarate\nMediated Inhibition of the\n                    <i>Leishmania<\/i>\n                    Inositol Phosphorylceramide\nSynthase"],"prefix":"10.1021","volume":"7","author":[{"given":"John G. M.","family":"Mina","sequence":"first","affiliation":[{"name":"University of Durham, Science Laboratories , , South Road , ,","place":["Durham, United Kingdom, DH1 3LE"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca L.","family":"Charlton","sequence":"additional","affiliation":[{"name":"University of Durham, Science Laboratories , , South Road , ,","place":["Durham, United Kingdom, DH1 3LE"]},{"name":"Universidade Federal do Rio de Janeiro , , , ,","place":["Rio de Janeiro, Rio de Janeiro, Brazil, 21941-902"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edubiel","family":"Alpizar-Sosa","sequence":"additional","affiliation":[{"name":"University of Durham , , South Road , ,","place":["Durham, United Kingdom, DH1 3LE"]},{"name":"University of Glasgow , , ,","place":["Glasgow, United Kingdom, G12 8TA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas O.","family":"Escrivani","sequence":"additional","affiliation":[{"name":"University of Durham, Science Laboratories , , South Road , ,","place":["Durham, United Kingdom, DH1 3LE"]},{"name":"Universidade Federal do Rio de Janeiro , , , ,","place":["Rio de Janeiro, Rio de Janeiro, Brazil, 21941-902"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher","family":"Brown","sequence":"additional","affiliation":[{"name":"University of Durham, Science Laboratories , , South Road , ,","place":["Durham, United Kingdom, DH1 3LE"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amjed","family":"Alqaisi","sequence":"additional","affiliation":[{"name":"University of Durham , , South Road , ,","place":["Durham, United Kingdom, DH1 3LE"]},{"name":"University of Baghdad , , ,","place":["Baghdad, Iraq, 10071"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Paula G.","family":"Borsodi","sequence":"additional","affiliation":[{"name":"Universidade Federal do Rio de Janeiro , , , ,","place":["Rio de Janeiro, Rio de Janeiro, Brazil, 21941-902"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia P.","family":"Figueiredo","sequence":"additional","affiliation":[{"name":"Universidade Federal do Rio de Janeiro , , , ,","place":["Rio de Janeiro, Rio de Janeiro, Brazil, 21944-590"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuelle V.","family":"de Lima","sequence":"additional","affiliation":[{"name":"Universidade Federal do Rio de Janeiro , , , ,","place":["Rio de Janeiro, Rio de Janeiro, Brazil, 21944-590"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Dickie","sequence":"additional","affiliation":[{"name":"University of Glasgow , , ,","place":["Glasgow, United Kingdom, G12 8TA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbin","family":"Wei","sequence":"additional","affiliation":[{"name":"University of Durham , , South Road , ,","place":["Durham, United Kingdom, DH1 3LE"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robson","family":"Coutinho-Silva","sequence":"additional","affiliation":[{"name":"Universidade Federal do Rio de Janeiro , , , ,","place":["Rio de Janeiro, Rio de Janeiro, Brazil, 21941-902"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Merritt","sequence":"additional","affiliation":[{"name":"LifeArc , Open Innovation Campus, ,","place":["Stevenage, United Kingdom, SG1 2FX"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1994-2009","authenticated-orcid":true,"given":"Terry K.","family":"Smith","sequence":"additional","affiliation":[{"name":"University of St Andrews , , North Haugh, ,","place":["St Andrews, United 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