title: Evaluation of nucleoside hydrolase inhibitors for treatment of African trypanosomiasis.
abstract: 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 inosine-adenosine-guanosine nucleoside hydrolase (IAG-NH). However, when the compounds were 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 significant activity (mean 50% inhibitory concentration [IC(50)] +/- standard error, 0.49 +/- 0.31 microM). 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 inosine-guanosine nucleoside hydrolase (IG-NH) to confirm the previously demonstrated inhibitory effects of the compounds on T. vivax IAG-NH. Second, to verify the uptake of these compounds by T. b. brucei, their affinities for the nucleoside P1 and nucleoside/nucleobase P2 transporters of T. b. brucei were tested. Only UAMC-00363 displayed significant affinity for the P2 transporter. It was also shown that UAMC-00363 is concentrated in the cell via at least one additional transporter, since P2 knockout mutants of T. b. brucei displayed no resistance to the compound. Consequently, no cross-resistance to 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 methylthioadenosine phosphorylase [MTAP]) were investigated using RNA interference. The findings from 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 that, therefore, it is possible that UAMC-00363 acts on an additional target.
authors.affiliation: Laboratory of Medicinal Chemistry, University of Antwerp, Antwerp, Belgium.
authors.forename: Maya
authors.initials: M
authors.lastname: Berg
authors.forename: Linda
authors.initials: L
authors.lastname: Kohl
authors.forename: Pieter
authors.initials: P
authors.lastname: Van der Veken
authors.forename: Jurgen
authors.initials: J
authors.lastname: Joossens
authors.forename: Mohammed I
authors.initials: MI
authors.lastname: Al-Salabi
authors.forename: Valeria
authors.initials: V
authors.lastname: Castagna
authors.forename: Francesca
authors.initials: F
authors.lastname: Giannese
authors.forename: Paul
authors.initials: P
authors.lastname: Cos
authors.forename: Wim
authors.initials: W
authors.lastname: Versées
authors.forename: Jan
authors.initials: J
authors.lastname: Steyaert
authors.forename: Philippe
authors.initials: P
authors.lastname: Grellier
authors.forename: Achiel
authors.initials: A
authors.lastname: Haemers
authors.forename: Massimo
authors.initials: M
authors.lastname: Degano
authors.forename: Louis
authors.initials: L
authors.lastname: Maes
authors.forename: Harry P
authors.initials: HP
authors.lastname: de Koning
authors.forename: Koen
authors.initials: K
authors.lastname: Augustyns
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D000981:Antiprotozoal Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D002352:Carrier Proteins / Q000378:metabolism; D055785:Gene Knockdown Techniques; D008549:Melarsoprol / Q000737:chemistry; D051379:Mice; D008956:Models, Chemical; D009699:N-Glycosyl Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics; D010419:Pentamidine / Q000737:chemistry; D034741:RNA, Small Interfering; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D002352:Carrier Proteins; C550934:N-(9-deazaadenin-9-yl)methyl-1,4-dideoxy-1,4-iminoribitol; D034741:RNA, Small Interfering; D010419:Pentamidine; D009699:N-Glycosyl Hydrolases; D000241:Adenosine; D008549:Melarsoprol