9-(2 '-Deoxy-2 '-Fluoro-beta-D-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance

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Ranjbarian, FarahnazUmeå universitet,Institutionen för medicinsk kemi och biofysik (author)

9-(2 '-Deoxy-2 '-Fluoro-beta-D-Arabinofuranosyl) Adenine Is a Potent Antitrypanosomal Adenosine Analogue That Circumvents Transport-Related Drug Resistance

Article/chapterEnglish2017

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American Society for Microbiology,2017
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LIBRIS-ID:oai:DiVA.org:umu-137649
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-137649URI
https://doi.org/10.1128/AAC.02719-16DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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Current chemotherapy against African sleeping sickness, a disease caused by the protozoan parasite Trypanosoma brucei, is limited by toxicity, inefficacy, and drug resistance. Nucleoside analogues have been successfully used to cure T. 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 in T. brucei. We report here that adenine arabinoside (Ara-A) and the newly tested drug 9-(2'-deoxy-2'-fluoro-beta-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 protects T. brucei 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 T. brucei adenosine kinase had a higher catalytic efficiency with FANA-A than the mammalian enzyme, and T. brucei 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(50)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 T. brucei-infected mice, but FANA-A did so at a dose 100 times lower than that of Ara-A.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Mikrobiologi inom det medicinska området hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Microbiology in the medical area hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Farmakologi och toxikologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Pharmacology and Toxicology hsv//eng
9-(2 '-deoxy-2 '-fluoro-beta-D-arabinofuranosyl) adenine
FANA-A
Trypanosoma brucei
adenosine kinase
drug resistance
methylthioadenosine phosphorylase
nucleoside transporters
trypanosome

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Vodnala, MunenderUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)murvoa04 (author)
Alzahrani, Khalid J. H. (author)
Ebiloma, Godwin U. (author)
de Koning, Harry P. (author)
Hofer, AndersUmeå universitet,Institutionen för medicinsk kemi och biofysik(Swepub:umu)anho0002 (author)
Umeå universitetInstitutionen för medicinsk kemi och biofysik (creator_code:org_t)

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In:Antimicrobial Agents and Chemotherapy: American Society for Microbiology61:60066-48041098-6596

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