New azasterols against Trypanosoma brucei: role of 24-sterol methyltransferase in inhibitor action.


Gros, L; Castillo-Acosta, VM; Jimenez Jimenez, C; Sealey-Cardona, M; Vargas, S; Manuel Estevez, A; Yardley, V; Rattray, L; Croft, SL; Ruiz-Perez, LM; Urbina, JA; Gilbert, IH; Gonzalez-Pacanowska, D; (2006) New azasterols against Trypanosoma brucei: role of 24-sterol methyltransferase in inhibitor action. Antimicrobial agents and chemotherapy, 50 (8). pp. 2595-601. ISSN 0066-4804 DOI: https://doi.org/10.1128/AAC.01508-05

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Abstract

A series of azasterol derivatives, designed as potential inhibitors of the Delta(24)-sterol methyltransferase enzyme (24-SMT), were synthesized and evaluated for their activities against parasitic protozoa. Values in the nanomolar range were obtained for 50% effective dose against the Trypanosoma brucei subsp. rhodesiense bloodstream form cultured in vitro. In order to investigate the mode of action, Trypanosoma brucei subsp. brucei 24-SMT was cloned and overexpressed and compounds were assayed for inhibitory activity. None of the inhibitors tested appeared to be active against the enzyme. Sterol composition analysis showed that only cholestane type sterols are present in membranes of bloodstream forms while ergosterol is a major component of procyclic sterol extracts. Interestingly, Northern blot analysis showed the presence of 24-SMT mRNA in both the procyclic and the bloodstream forms of the parasite, although levels of mRNA were threefold lower in the latter. Likewise, Western blot analysis and activity determinations evidenced the existence of active enzyme in both forms of the parasite. We conclude that the designed compounds act at sites other than 24-SMT in Trypanosoma brucei.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Research Centre: Neglected Tropical Diseases Network
PubMed ID: 16870747
Web of Science ID: 239640400001
URI: http://researchonline.lshtm.ac.uk/id/eprint/11597

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