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Investigation of trypanothione reductase as a drug target in Trypanosoma brucei.
ChemMedChem. 2009 Dec; 4(12):2060-9.C

Abstract

There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62,000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel-compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed.

Authors+Show Affiliations

Drug Discovery Unit, College of Life Sciences, University of Dundee, Sir James Black Centre, Dundee, DD1 5EH, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19924760

Citation

Spinks, Daniel, et al. "Investigation of Trypanothione Reductase as a Drug Target in Trypanosoma Brucei." ChemMedChem, vol. 4, no. 12, 2009, pp. 2060-9.
Spinks D, Shanks EJ, Cleghorn LA, et al. Investigation of trypanothione reductase as a drug target in Trypanosoma brucei. ChemMedChem. 2009;4(12):2060-9.
Spinks, D., Shanks, E. J., Cleghorn, L. A., McElroy, S., Jones, D., James, D., Fairlamb, A. H., Frearson, J. A., Wyatt, P. G., & Gilbert, I. H. (2009). Investigation of trypanothione reductase as a drug target in Trypanosoma brucei. ChemMedChem, 4(12), 2060-9. https://doi.org/10.1002/cmdc.200900262
Spinks D, et al. Investigation of Trypanothione Reductase as a Drug Target in Trypanosoma Brucei. ChemMedChem. 2009;4(12):2060-9. PubMed PMID: 19924760.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Investigation of trypanothione reductase as a drug target in Trypanosoma brucei. AU - Spinks,Daniel, AU - Shanks,Emma J, AU - Cleghorn,Laura A T, AU - McElroy,Stuart, AU - Jones,Deuan, AU - James,Daniel, AU - Fairlamb,Alan H, AU - Frearson,Julie A, AU - Wyatt,Paul G, AU - Gilbert,Ian H, PY - 2009/11/20/entrez PY - 2009/11/20/pubmed PY - 2010/3/10/medline SP - 2060 EP - 9 JF - ChemMedChem JO - ChemMedChem VL - 4 IS - 12 N2 - There is an urgent need for new drugs for the treatment of tropical parasitic diseases such as human African trypanosomiasis, which is caused by Trypanosoma brucei. The enzyme trypanothione reductase (TryR) is a potential drug target within these organisms. Herein we report the screening of a 62,000 compound library against T. brucei TryR. Further work was undertaken to optimise potency and selectivity of two novel-compound series arising from the enzymatic and whole parasite screens and mammalian cell counterscreens. Both of these series, containing either a quinoline or pyrimidinopyrazine scaffold, yielded low micromolar inhibitors of the enzyme and growth of the parasite. The challenges of inhibiting TryR with druglike molecules is discussed. SN - 1860-7187 UR - https://www.unboundmedicine.com/medline/citation/19924760/Investigation_of_trypanothione_reductase_as_a_drug_target_in_Trypanosoma_brucei_ L2 - https://doi.org/10.1002/cmdc.200900262 DB - PRIME DP - Unbound Medicine ER -