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

Abstract

S U M M A R YCyclophilins 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.

Molecular characterization of Cyclophilin (TcCyP19) in Trypanosoma cruzi populations susceptible and resistant to benznidazole

“…These data suggest that CyPA is a good target for cancer chemotherapy. Interestingly, some studies suggest that TcCyPs are promising targets for the treatment of Chagas disease (Búa et al, 2008;Carraro et al, 2007). Cyclophilins bind cyclosporin A (CsA), an immunosuppressive antimicrobial drug, and nonimmunosuppressive CsA analogues possess higher activity against T. cruzi (Búa et al, 2008).…”

“…Interestingly, some studies suggest that TcCyPs are promising targets for the treatment of Chagas disease (Búa et al, 2008;Carraro et al, 2007). Cyclophilins bind cyclosporin A (CsA), an immunosuppressive antimicrobial drug, and nonimmunosuppressive CsA analogues possess higher activity against T. cruzi (Búa et al, 2008). In conclusion, given that our results show that TcCyP19 is upregulated in BZ-resistant T. cruzi populations and that several lines of evidence implicate CyPs as a promising chemotherapeutic target against cancer and parasitic diseases, our work constitutes a starting point for further investigation into the role of TcCyPs in the mechanism of drug resistance and as a target for Chagas disease chemotherapy.…”

Secreted Trypanosome Cyclophilin Inactivates Lytic Insect Defense Peptides and Induces Parasite Calcineurin Activation and Infectivity

“…The T. cruzi genome contains genes encoding 15 cyclophilin orthologs at least 4 of which bind to and are inhibited by cyclosporine A, including cyclophilin 19 (24,35), yet until now the function of individual parasite cyclophilins has not been determined. Numerous cyclophilin genes are also present in the related parasites Leishmania (36) and T. brucei (14,24,37), and cyclophilin 19 homologs of that secreted from T. cruzi are also secreted from these parasites (Fig.…”

P-glycoprotein efflux pump plays an important role in Trypanosoma cruzi drug resistance

“…The parental and resistant lines were resuspended at a density of 5 × 10 6  parasites/mL in phosphate-buffered saline (PBS), and the resistant lines were incubated at 26 °C for 15 min in the presence or absence of 2 μM of the Pgp inhibitors verapamil or cyclosporin A (Búa et al 2008). The parasites were then pelleted at 2,000× g for 10 min, resuspended in 1 ml PBS containing 20 μg/mL of Rhodamine 123 fluorescent probe, and incubated for 5 min at 26 °C.…”