What's new for 'Trypanosomatids' in PubMed

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Sent on Wednesday, 2010 Mar 03
Search kinetoplastids OR kinetoplastid OR Kinetoplastida OR "trypanosoma brucei" OR leishmania OR brucei OR leishmaniasis OR "African trypanosomiasis"
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PubMed Results

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1.	Antimicrob Agents Chemother. 2010 Mar 1. [Epub ahead of print] Evaluation of nucleoside hydrolase inhibitors for the treatment of African trypanosomiasis. 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. Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium; Muséum National d'Histoire Naturelle, USM 504-EA3335, Biologie Fonctionnelle des Protozoaires, 61 Rue Buffon, CP52, Paris Cedex 05, 75231, France; Institute of Biomedical and Life Sciences, Division of Infection and Immunity, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, UK; Biocrystallography Unit and Mass Spectrometry Unit, DIBIT San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy; Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium; Structural Biology Brussels, Vrije Unversiteit Brussel and Department of Molecular and Cellular Interactions, VIB, Pleinlaan 2, B-1050, Brussels, Belgium. 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 muM). 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.
	PMID: 20194690 [PubMed - as supplied by publisher]