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Nucleoside analogues have been successfully used to cure\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            -infected mice, but they have the limitation of mainly being taken up by the P2 nucleoside transporter, which, when mutated, is a common cause of multidrug resistance in\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            . We report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2\u2032-deoxy-2\u2032-fluoro-\u03b2-\n            <jats:sc>d<\/jats:sc>\n            -arabinofuranosyl) adenine (FANA-A) are instead taken up by the P1 nucleoside transporter, which is not associated with drug resistance. Like Ara-A, FANA-A was found to be resistant to cleavage by methylthioadenosine phosphorylase, an enzyme that protects\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            against the antitrypanosomal effects of deoxyadenosine. Another important factor behind the selectivity of nucleoside analogues is how well they are phosphorylated within the cell. We found that the\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            adenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, and\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            cells treated with FANA-A accumulated high levels of FANA-A triphosphate, which even surpassed the level of ATP and led to cell cycle arrest, inhibition of DNA synthesis, and the accumulation of DNA breaks. FANA-A inhibited nucleic acid biosynthesis and parasite proliferation with 50% effective concentrations (EC\n            <jats:sub>50<\/jats:sub>\n            s) in the low nanomolar range, whereas mammalian cell proliferation was inhibited in the micromolar range. Both Ara-A and FANA-A, in combination with deoxycoformycin, cured\n            <jats:named-content content-type=\"genus-species\">T. brucei<\/jats:named-content>\n            -infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.\n          <\/jats:p>","DOI":"10.1128\/aac.02719-16","type":"journal-article","created":{"date-parts":[[2017,4,4]],"date-time":"2017-04-04T00:37:41Z","timestamp":1491266261000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":10,"title":["9-(2\u2032-Deoxy-2\u2032-Fluoro-\u03b2-\n            <scp>d<\/scp>\n            -Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance"],"prefix":"10.1128","volume":"61","author":[{"given":"Farahnaz","family":"Ranjbarian","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Munender","family":"Vodnala","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Biophysics, Ume\u00e5 University, Ume\u00e5, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Khalid J. 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