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

Ranjbarian, Farahnaz (author): Umeå universitet,Institutionen för medicinsk kemi och biofysik

Vodnala, Munender (author): Umeå universitet,Institutionen för medicinsk kemi och biofysik

Alzahrani, Khalid J. H. (author)

Ebiloma, Godwin U. (author)

de Koning, Harry P. (author)

Hofer, Anders (author): Umeå universitet,Institutionen för medicinsk kemi och biofysik

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American Society for Microbiology, 2017
2017
English.
In: Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology. - 0066-4804 .- 1098-6596. ; 61:6

Related links:: https://urn.kb.se/re...; show more...; https://doi.org/10.1...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

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

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)

Keyword

9-(2 '-deoxy-2 '-fluoro-beta-D-arabinofuranosyl) adenine
FANA-A
Trypanosoma brucei
adenosine kinase
drug resistance
methylthioadenosine phosphorylase
nucleoside transporters
trypanosome

Publication and Content Type

ref (subject category)
art (subject category)

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