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

J.BÚA, L.E. FICHERA, A.FUCHS, M.POTENZA, M.DUBIN, R.O. WENGER, G.MORETTI, C.N.SCARBONE, A.M.RUIZ

PARASITOLOGY

Cambridge University Press

Lugar: Cambridge; Año: 2008 vol. 135 p. 217 - 228

0031-1820

SUMMARYCyclophilins are target molecules for cyclosporin A (CsA), an immunosuppressive antimicrobial drug. We have previouslyreported the in vitro anti-Trypanosoma cruzi activity of H-7-94 and F-7-62 non-immunosuppressive CsA analogues. In thiswork, we continue the study of the parasiticidal effect of H-7-94 and F-7-62 CsA analogues in vitro and in vivo and weanalyse 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 evidencedas inhibition of epimastigote proliferation, trypomastigote penetration, intracellular amastigote development and in vivoT. cruzi infection. This trypanocidal activity could be due to inhibition of the peptidyl prolyl cis-trans isomerase activity onthe T. cruzi recombinant cyclophilins tested. Furthermore, CsA and F-7-62 derivative inhibited the efflux of rhodamine123 from T. cruzi epimastigotes, suggesting an interference with a P-glycoprotein activity. Moreover, H-7-94 and F-7-62CsA 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.Key words: Trypanosoma cruzi, cyclosporin A derivatives, cyclophilins, P-glycoprotein, parasiticidal acti