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Treatment options are very limited and threatened by resistance. Tubercidin (7-deazaadenosine) analogs have shown activity against individual parasites but viable chemotherapy must be active against all three species. Divergence in sensitivity to nucleoside antimetabolites could be caused by differences in nucleoside transporters. Having previously characterized the T. brucei nucleoside carriers, we here report the functional expression and characterization of the main adenosine transporters of T. vivax (TvxNT3) and T. congolense (TcoAT1\/NT10), in a Leishmania mexicana cell line (\u2018SUPKO\u2019) lacking adenosine uptake. Both carriers were similar to the T. brucei P1-type transporters and bind adenosine mostly through interactions with N3, N7 and 3\u2032-OH. Expression of TvxNT3 and TcoAT1 sensitized SUPKO cells to various 7-substituted tubercidins and other nucleoside analogs although tubercidin itself is a poor substrate for P1-type transporters. Individual nucleoside EC50s were similar for T. b. brucei, T. congolense, T. evansi and T. equiperdum but correlated less well with T. vivax. However, multiple nucleosides including 7-halogentubercidines displayed pEC50&gt;7 for all species and, based on transporter and anti-parasite SAR analyses, we conclude that nucleoside chemotherapy for AAT is viable.<\/jats:p>","DOI":"10.3390\/ijms24043144","type":"journal-article","created":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T03:34:30Z","timestamp":1675654470000},"page":"3144","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Cloning and Characterization of Trypanosoma congolense and T. vivax Nucleoside Transporters Reveal the Potential of P1-Type Carriers for the Discovery of Broad-Spectrum Nucleoside-Based Therapeutics against Animal African Trypanosomiasis"],"prefix":"10.3390","volume":"24","author":[{"given":"Marzuq A.","family":"Ungogo","sequence":"first","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"},{"name":"Department of Veterinary Pharmacology and Toxicology, Ahmadu Bello University, Zaria 810107, Kaduna State, Nigeria"},{"name":"Roslin Institute, Royal (Dick) School of Veterinary Studies, University of Edinburgh, Midlothian EH25 9RG, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3998-7642","authenticated-orcid":false,"given":"Mustafa M.","family":"Aldfer","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manal J.","family":"Natto","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hainan","family":"Zhuang","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robyn","family":"Chisholm","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katy","family":"Walsh","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"MarieClaire","family":"McGee","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2955-5096","authenticated-orcid":false,"given":"Kayhan","family":"Ilbeigi","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, B-2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamal Ibrahim","family":"Asseri","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1663-9004","authenticated-orcid":false,"given":"Richard J. S.","family":"Burchmore","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4870-3202","authenticated-orcid":false,"given":"Guy","family":"Caljon","sequence":"additional","affiliation":[{"name":"Laboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, B-2610 Wilrijk, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4201-1264","authenticated-orcid":false,"given":"Serge","family":"Van Calenbergh","sequence":"additional","affiliation":[{"name":"Laboratory for Medicinal Chemistry (Campus Heymans), Ghent University, B-9000 Gent, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9963-1827","authenticated-orcid":false,"given":"Harry P.","family":"De Koning","sequence":"additional","affiliation":[{"name":"School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1862","DOI":"10.1017\/S0031182016001268","article-title":"The animal trypanosomiases and their chemotherapy: A review","volume":"143","author":"Giordani","year":"2016","journal-title":"Parasitology"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Franco, J.R., Cecchi, G., Priotto, G., Paone, M., Diarra, A., Grout, L., Simarro, P.P., Zhao, W., and Argaw, D. 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