title: 9-(2'-Deoxy-2'-Fluoro-β-d-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance.
abstract: Current chemotherapy against African sleeping sickness, a disease caused by the protozoan parasiteTrypanosoma brucei, is limited by toxicity, inefficacy, and drug resistance. Nucleoside analogues have been successfully used to cureT. brucei-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 inT. bruceiWe report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2'-deoxy-2'-fluoro-β-d-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 protectsT. bruceiagainst 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 theT. bruceiadenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, andT. bruceicells 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 (EC50s) 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, curedT. brucei-infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Ranjbarian
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
authors.forename: Munender
authors.initials: M
authors.lastname: Vodnala
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.|Department of Clinical Laboratory, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia.
authors.forename: Khalid J H
authors.initials: KJH
authors.lastname: Alzahrani
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Godwin U
authors.initials: GU
authors.lastname: Ebiloma
authors.affiliation: Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
authors.affiliation: Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden anders.hofer@umu.se.
authors.forename: Anders
authors.initials: A
authors.lastname: Hofer
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives*; D000248:Adenosine Kinase / Q000235:genetics; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology / Q000627:therapeutic use; D004351:Drug Resistance / Q000235:genetics; D051379:Mice; D011683:Purine-Nucleoside Phosphorylase / Q000235:genetics; D014345:Trypanosoma / Q000187:drug effects / Q000378:metabolism; D014346:Trypanosoma brucei brucei / Q000187:drug effects / Q000378:metabolism; D014353:Trypanosomiasis, African / Q000188:drug therapy
chemical_list: D000963:Antimetabolites; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D000248:Adenosine Kinase; D000225:Adenine
keywords: 9-(2′-deoxy-2′-fluoro-β-d-arabinofuranosyl) adenine; FANA-A; Trypanosoma brucei; adenosine kinase; drug resistance; methylthioadenosine phosphorylase; nucleoside transporters; trypanosome