Evaluation of nucleoside hydrolase inhibitors for treatment of african trypanosomiasis

Maya Berg, Linda Kohl, Pieter Van Der Veken, Jurgen Joossens, Mohammed I. Al-Salabi, Valeria Castagna, Francesca Giannese, Paul Cos, Wim Versées, Jan Steyaert, Philippe Grellier, Achiel Haemers, Massimo Degano, Louis Maes, Harry P. De Koning, Koen Augustyns

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 [IC50] ± standard error, 0.49 ± 0.31 μM). 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 inosineguanosine 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.

Original languageEnglish
Pages (from-to)1900-1908
Number of pages9
JournalAntimicrobial Agents and Chemotherapy
Volume54
Issue number5
DOIs
Publication statusPublished - May 2010

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N-Glycosyl Hydrolases
African Trypanosomiasis
Trypanosoma vivax
Nucleosides
Inhibitory Concentration 50
Trypanocidal Agents
Ribitol
Arsenicals
Pentamidine
Antiparasitic Agents
Trypanosoma brucei brucei
Trypanosomiasis
RNA Interference
Libraries
N-(9-deazaadenin-9-yl)methyl-1,4-dideoxy-1,4-iminoribitol
inosine-adenosine-guanosine-preferring nucleoside hydrolase
Enzymes

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Berg, M., Kohl, L., Van Der Veken, P., Joossens, J., Al-Salabi, M. I., Castagna, V., ... Augustyns, K. (2010). Evaluation of nucleoside hydrolase inhibitors for treatment of african trypanosomiasis. Antimicrobial Agents and Chemotherapy, 54(5), 1900-1908. https://doi.org/10.1128/AAC.01787-09

Evaluation of nucleoside hydrolase inhibitors for treatment of african trypanosomiasis. / Berg, Maya; Kohl, Linda; Van Der Veken, Pieter; Joossens, Jurgen; Al-Salabi, Mohammed I.; Castagna, Valeria; Giannese, Francesca; Cos, Paul; Versées, Wim; Steyaert, Jan; Grellier, Philippe; Haemers, Achiel; Degano, Massimo; Maes, Louis; De Koning, Harry P.; Augustyns, Koen.

In: Antimicrobial Agents and Chemotherapy, Vol. 54, No. 5, 05.2010, p. 1900-1908.

Research output: Contribution to journalArticle

Berg, M, Kohl, L, Van Der Veken, P, Joossens, J, Al-Salabi, MI, Castagna, V, Giannese, F, Cos, P, Versées, W, Steyaert, J, Grellier, P, Haemers, A, Degano, M, Maes, L, De Koning, HP & Augustyns, K 2010, 'Evaluation of nucleoside hydrolase inhibitors for treatment of african trypanosomiasis', Antimicrobial Agents and Chemotherapy, vol. 54, no. 5, pp. 1900-1908. https://doi.org/10.1128/AAC.01787-09
Berg M, Kohl L, Van Der Veken P, Joossens J, Al-Salabi MI, Castagna V et al. Evaluation of nucleoside hydrolase inhibitors for treatment of african trypanosomiasis. Antimicrobial Agents and Chemotherapy. 2010 May;54(5):1900-1908. https://doi.org/10.1128/AAC.01787-09
Berg, Maya ; Kohl, Linda ; Van Der Veken, Pieter ; Joossens, Jurgen ; Al-Salabi, Mohammed I. ; Castagna, Valeria ; Giannese, Francesca ; Cos, Paul ; Versées, Wim ; Steyaert, Jan ; Grellier, Philippe ; Haemers, Achiel ; Degano, Massimo ; Maes, Louis ; De Koning, Harry P. ; Augustyns, Koen. / Evaluation of nucleoside hydrolase inhibitors for treatment of african trypanosomiasis. In: Antimicrobial Agents and Chemotherapy. 2010 ; Vol. 54, No. 5. pp. 1900-1908.
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