Evaluation of Nucleoside Hydrolase Inhibitors for Treatment of African Trypanosomiasis

Author:

Berg Maya1,Kohl Linda2,Van der Veken Pieter1,Joossens Jurgen1,Al-Salabi Mohammed I.3,Castagna Valeria4,Giannese Francesca4,Cos Paul5,Versées Wim6,Steyaert Jan6,Grellier Philippe2,Haemers Achiel1,Degano Massimo4,Maes Louis5,de Koning Harry P.3,Augustyns Koen1

Affiliation:

1. Laboratory of Medicinal Chemistry, University of Antwerp, Universiteitsplein 1, B-2610 Antwerp, Belgium

2. Muséum National d'Histoire Naturelle, USM 504-EA3335, Biologie Fonctionnelle des Protozoaires, 61 Rue Buffon, CP52, Paris Cedex 05 75231, France

3. Institute of Biomedical and Life Sciences, Division of Infection and Immunity, Glasgow Biomedical Research Centre, University of Glasgow, 120 University Place, Glasgow G12 8TA, United Kingdom

4. Biocrystallography Unit and Mass Spectrometry Unit, DIBIT San Raffaele Scientific Institute, via Olgettina 58, 20132 Milan, Italy

5. Laboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Groenenborgerlaan 171, B-2020 Antwerp, Belgium

6. Structural Biology Brussels, Vrije Unversiteit Brussel, and Department of Molecular and Cellular Interactions, VIB, Pleinlaan 2, B-1050 Brussels, Belgium

Abstract

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 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 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.

Publisher

American Society for Microbiology

Subject

Infectious Diseases,Pharmacology (medical),Pharmacology

Reference43 articles.

1. Absalon, S., L. Kohl, C. Branche, T. Blisnick, G. Toutirais, F. Rusconi, J. Cosson, Bonhivers, D. Robinson, and P. Bastin. 2007. Basal body positioning is controlled by flagellum formation in Trypanosoma brucei. PLoS One2:e437.

2. Al-Salabi, M. I., L. J. M. Wallace, A. Lüscher, P. Mäser, D. Candlish, B. Rodenko, M. K. Gould, I. Jabeen, S. N. Ajith, and H. P. de Koning. 2007. Molecular interactions underlying the unusually high adenosine affinity of a novel Trypanosoma brucei nucleoside transporter. Mol. Pharmacol.71:921-929.

3. Barrett, M. P., and I. H. Gilbert. 2006. Targeting of toxic compounds to the trypanosome's interior. Adv. Parasitol.63:125-183.

4. Berg, M., G. Bal, A. Goeminne, P. Van der Veken, W. Versées, J. Steyaert, A. Haemers, and K. Augustyns. 2009. Synthesis of bicyclic N-arylmethyl substituted iminoribitol derivatives as selective nucleoside hydrolase inhibitors. ChemMedChem4:249-260.

5. Berriman, M., E. Ghedin, C. Hertz-Fowler, G. Blandin, H. Renauld, D. C. Bartholomeu, N. J. Lennard, E. Caler, N. E. Hamlin, B. Haas, U. Boehme, L. Hannick, M. A. Aslett, J. M. L. Shallom, L. Hou, B. Wickstead, U. C. M. Alsmark, C. Arrowsmith, R. J. Atkin, A. J. Barron, F. Bringaud, K. Brooks, M. Carrington, I. Cherevach, T.-J. Chillingworth, C. Churcher, L. N. Clark, C. H. Corton, A. Cronin, R. M. Davies, J. Doggett, A. Djikeng, T. Feldblyum, M. C. Field, A. Fraser, I. Goodhead, Z. Hance, D. Harper, B. R. Harris, H. Hauser, J. Hostetler, A. Ivens, K. Jagels, D. Johnson, J. Johnson, K. Jones, A. X. Kerhornou, H. Koo, N. Larke, S. Landfear, C. Larkin, V. Leech, A. Line, A. Lord, A. MacLeod, P. J. Mooney, S. Moule, D. M. A. Martin, G. W. Morgan, K. Mungall, H. Norbertczak, D. Ormond, G. Pai, C. S. Peacock, J. Peterson, M. A. Quail, E. Rabbinowitsch, M.-A. Rajandream, C. Reitter, S. L. Salzberg, M. Sanders, S. Schobel, S. Sharp, M. Simmonds, A. J. Simpson, L. Tallon, C. Turner, R. Michael, A. Tait, A. R. Tivey, S. Van Aken, D. Walker, D. Wanless, S. Wang, B. White, O. White, S. Whitehead, J. Woodward, J. Wortman, M. D. Adams, T. M. Embley, K. Gull, E. Ullu, J. D. Barry,. H. Fairlamb, F. Opperdoes, B. G. Barrell, J. E. Donelson, N. Hall, C. M. Fraser, S. E. Melville, and N. M. El-Sayed. 2005. The genome of the African trypanosome Trypanosoma brucei. Science309:416-422.

Cited by 39 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3