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Artículo

Evaluation of proline analogs as trypanocidal agents through the inhibition of a Trypanosoma cruzi proline transporter

Martínez Sayé, Melisa SoledadIcon ; Fargnoli, LucíaIcon ; Reigada, ChantalIcon ; Labadie, Guillermo RobertoIcon ; Pereira, Claudio AlejandroIcon
Fecha de publicación: 08/2017
Editorial: Elsevier Science
Revista: Biochimica et Biophysica Acta- General Subjects
ISSN: 0304-4165
Idioma: Inglés
Tipo de recurso: Artículo publicado
Clasificación temática:
Otras Ciencias Biológicas

Resumen

Background: Trypanosoma cruzi, the etiological agent of Chagas disease, uses proline as its main carbon source, essential for parasite growth and stage differentiation in epimastigotes and amastigotes. Since proline is involved in many essential biological processes in T. cruzi, its transport and metabolism are interesting drug targets. Methods: Four synthetic proline analogues (ITP-1B/1C/1D/1G) were evaluated as inhibitors of proline transport mediated through the T. cruzi proline permease TcAAAP069. The trypanocidal activity of the compounds was also assessed. Results: The compounds ITP-1B and ITP-1G inhibited proline transport mediated through TcAAAP069 permease in a dose-dependent manner. The analogues ITP-1B, -1D and -1G had trypanocidal effect on T. cruzi epimastigotes with IC50 values between 30 and 40μM. However, only ITP-1G trypanocidal activity was related with its inhibitory effect on TcAAAP069 proline transporter. Furthermore, this analogue strongly inhibited the parasite stage differentiation from epimastigote to metacyclic trypomastigote. Finally, compounds ITP-1B and ITP-1G were also able to inhibit the transport mediated by other permeases from the same amino acid permeases family, TcAAAP. Conclusions: It is possible to design synthetic amino acid analogues with trypanocidal activity. The compound ITP-1G is an interesting starting point for new trypanocidal drug design which is also an inhibitor of transport of amino acids and polyamines mediated by permeases from the TcAAAP family, such as proline transporter TcAAAP069 among others. General significance: The Trypanosoma cruzi amino acid transporter family TcAAAP constitutes a multiple and promising therapeutic target for the development of new treatments against Chagas disease.
Palabras clave: Amino Acid Transport , Proline Analogues , Transport Inhibition , Trypanocidal Effect , Trypanosoma Cruzi
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info:eu-repo/semantics/openAccess Excepto donde se diga explícitamente, este item se publica bajo la siguiente descripción: Creative Commons Attribution-NonCommercial-ShareAlike 2.5 Unported (CC BY-NC-SA 2.5)
Identificadores
URI: http://hdl.handle.net/11336/47213
DOI: https://dx.doi.org/10.1016/j.bbagen.2017.08.015
URL: https://www.sciencedirect.com/science/article/pii/S0304416517302714
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Articulos(IDIM)
Articulos de INST.DE INVEST.MEDICAS
Citación
Martínez Sayé, Melisa Soledad; Fargnoli, Lucía; Reigada, Chantal; Labadie, Guillermo Roberto; Pereira, Claudio Alejandro; Evaluation of proline analogs as trypanocidal agents through the inhibition of a Trypanosoma cruzi proline transporter; Elsevier Science; Biochimica et Biophysica Acta- General Subjects; 1861; 11; 8-2017; 2913-2921
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