9-(2' -Deoxy-2' -fluoro-ß-D-arabinofuranosyl) adenine: a potent antitrypanosomal adenosine analogue that circumvents transport-related drug resistance

Ranjbarian, F., Vodnala, M., Alzahrani, K. J.H., Ebiloma, G. U., de Koning, H. P. and Hofer, A. (2017) 9-(2' -Deoxy-2' -fluoro-ß-D-arabinofuranosyl) adenine: a potent antitrypanosomal adenosine analogue that circumvents transport-related drug resistance. Antimicrobial Agents and Chemotherapy, 61(6), e02719-16. (doi:10.1128/AAC.02719-16) (PMID:28373184) (PMCID:PMC5444181)

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Abstract

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 all have the limitation of 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-ß-D-arabinofuranosyl) adenine (FANA-A) are instead taken up by the P1 nucleoside transporter, which is not associated with drug resistance. Similar to Ara-A, FANA-A was also 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 accumulation of DNA breaks. FANA-A inhibited nucleic acid biosynthesis and parasite proliferation with EC50 values 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 100 times lower dose than Ara-A.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Alzahrani, Khalid Jamaan and De Koning, Professor Harry
Authors: Ranjbarian, F., Vodnala, M., Alzahrani, K. J.H., Ebiloma, G. U., de Koning, H. P., and Hofer, A.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:Antimicrobial Agents and Chemotherapy
Publisher:American Society for Microbiology
ISSN:0066-4804
ISSN (Online):1098-6596
Published Online:03 April 2017
Copyright Holders:Copyright © 2017 American Society for Microbiology
First Published:First published in Antimicrobial Agents and Chemotherapy 61(6): e02719-16
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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