Evaluation of nucleoside hydrolase inhibitors for the treatment of African trypanosomiasisEvaluation of nucleoside hydrolase inhibitors for the treatment of African trypanosomiasis
Faculty of Social Sciences. Sociology
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences. Pharmacy
Medicinal Chemistry (UAMC)
Laboratory for Microbiology, Parasitology and Hygiene (LMPH)
2010Washington, D.C., 2010
Antimicrobial agents and chemotherapy. - Washington, D.C.
54(2010):5, p. 1900-1908
University of Antwerp
In this paper we present the biochemical and biological evaluation of N-arylmethyl-substituted iminoribitol derivatives as potential chemotherapeutic agents against trypanosomiasis. Previously, a library of 52 compounds was designed and synthesized as potent and selective inhibitors of Trypanosoma vivax IAG-NH. However, when tested against bloodstream form Trypanosoma brucei brucei, only one inhibitor, N-(9-deaza-adenin-9-yl)methyl-1,4-dideoxy-1,4-imino-D-ribitol (UAMC-00363), displayed a significant activity (IC50 = 0.49 ± 0.31 μM). A validation in an in vivo model of African trypanosomiasis showed promising results for this compound. Several experiments were performed to investigate why only UAMC-00363 showed antiparasitic activity. First, the compound library was screened against T. b. brucei IAG-NH and IG-NH to confirm the inhibitory effect of the compounds previously demonstrated on T. vivax IAG-NH. Second, to verify the uptake of these compounds by T. b. brucei, their affinity for the nucleoside P1 and nucleoside/nucleobase P2 transporter of T. b. brucei was tested. Only UAMC-00363 displayed a significant affinity towards the P2 transporter. It was also shown that UAMC-00363 is concentrated into the cell via at least one additional transporter, since it displayed no resistance against P2 knockout mutants of T. b. brucei. Consequently, no cross-resistance with the diamidine or the melaminophenyl arsenical classes of trypanocides is expected. Third, three enzymes of the purine salvage pathway of procyclic T. b. brucei (IAG-NH, IG-NH and MTAP) were investigated using RNAi knockdown. All these studies showed that it is probably not sufficient to target only the nucleoside hydrolase activity to block the purine salvage pathway of T. b. brucei and therefore it is possible that UAMC-00363 acts on an additional target.