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Anti-Trypanosoma cruzi effects of cyclosporin A derivatives: possible role of a P-glycoprotein and parasite cyclophilins

Published online by Cambridge University Press:  09 October 2007

J. BÚA ,
L. E. FICHERA ,
A. G. FUCHS ,
M. POTENZA ,
M. DUBIN ,
R. O. WENGER ,
G. MORETTI ,
C. M. SCABONE  and
A. M. RUIZ
J. BÚA*
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
L. E. FICHERA
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
A. G. FUCHS
Affiliation:
Centro de Estudios Farmacológicos y Botánicos, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina Centro de altos estudios de Ciencias de la Salud, Universidad Abierta Interamericana, Buenos Aires, Argentina
M. POTENZA
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
M. DUBIN
Affiliation:
Centro de Estudios Farmacológicos y Botánicos, Facultad de Medicina, Universidad de Buenos Aires, Buenos Aires, Argentina
R. O. WENGER
Affiliation:
Wenger Chemtech, CH-4125Riehen, Switzerland
G. MORETTI
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
C. M. SCABONE
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
A. M. RUIZ
Affiliation:
Instituto Nacional de Parasitología “Dr. Mario Fatala Chabén”ANLIS Carlos G. Malbrán, Buenos Aires, Argentina
*
*Corresponding author: Av. Paseo Colón 568 (1063)Buenos Aires, Argentina. Tel: +5411 4331 4010. Fax: +5411 4331 7142. E-mail: jacbua@yahoo.com
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Summary

Cyclophilins are target molecules for cyclosporin A (CsA), an immunosuppressive antimicrobial drug. We have previously reported the in vitro anti-Trypanosoma cruzi activity of H-7-94 and F-7-62 non-immunosuppressive CsA analogues. In this work, we continue the study of the parasiticidal effect of H-7-94 and F-7-62 CsA analogues in vitro and in vivo and we analyse 3 new CsA derivatives: MeIle-4-CsA (NIM 811), MeVal-4-CsA (MeVal-4) and D-MeAla-3-EtVal-4-CsA, (EtVal-4). The most efficient anti-T. cruzi effect was observed with H-7-94, F-7-62 and MeVal-4 CsA analogues evidenced as inhibition of epimastigote proliferation, trypomastigote penetration, intracellular amastigote development and in vivo T. cruzi infection. This trypanocidal activity could be due to inhibition of the peptidyl prolyl cis-trans isomerase activity on the T. cruzi recombinant cyclophilins tested. Furthermore, CsA and F-7-62 derivative inhibited the efflux of rhodamine 123 from T. cruzi epimastigotes, suggesting an interference with a P-glycoprotein activity. Moreover, H-7-94 and F-7-62 CsA analogues were not toxic as shown by cell viability and by aminopyrine-N-demethylase activity on mammalian cells. Our results show that H-7-94, F-7-62 and MeVal-4 CsA analogues expressed the highest inhibiting effects on T. cruzi, being promissory parasiticidal drugs worthy of further studies.

Keywords

Trypanosoma cruzicyclosporin A derivativescyclophilinsP-glycoproteinparasiticidal activity
Type
Research Article
Information
Parasitology , Volume 135 , Issue 2 , February 2008 , pp. 217 - 228
Copyright
Copyright © Cambridge University Press 2007

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