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Antimicrobial Agents and Chemotherapy, August 2006, p. 2595-2601, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.01508-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

New Azasterols against Trypanosoma brucei: Role of 24-Sterol Methyltransferase in Inhibitor Action

Ludovic Gros,¹ Victor Manuel Castillo-Acosta,² Carmen Jiménez Jiménez,² Marco Sealey-Cardona,² Sofia Vargas,² Antonio Manuel Estévez,² Vanessa Yardley,³ Lauren Rattray,³ Simon L. Croft,³ Luis M. Ruiz-Perez,² Julio A. Urbina,⁴ Ian H. Gilbert,¹ and Dolores González Pacanowska^2*

Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, United Kingdom,¹ Instituto de Parasitología y Biomedicina López-Neyra, Parque Tecnológico de Ciencias de la Salud, Avenida del Conocimiento s/n, 18100 Armilla, Granada, Spain,² Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom,³ Laboratorio de Química Biológica, Centro de Bioquímica y Biofísica, Instituto Venezolano de Investigaciones Científicas (IVIC), Altos de Pipe, Km. 11, Carretera Panamericana, Caracas 1020, Venezuela⁴

Received 23 November 2005/ Returned for modification 3 January 2006/ Accepted 5 May 2006

A series of azasterol derivatives, designed as potential inhibitors of the 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.

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* Corresponding author. Mailing address: Instituto de Parasitología y Biomedicina López-Neyra, Consejo Superior de Investigaciones Científicas, Avda. del Conocimiento s/n, Parque Tecnológico de Ciencias de la Salud, 18100 Armilla, Granada, Spain. Phone: 34 958 181621. Fax: 34 958 181633. E-mail: dgonzalez{at}ipb.csic.es.

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Antimicrobial Agents and Chemotherapy, August 2006, p. 2595-2601, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.01508-05
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

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