Anti-Trypanosoma cruzi effects of cyclosporin A derivatives: possible role of a P-glycoprotein and parasite cyclophilins.
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.
Búa
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Instituto Nacional de Parasitología Dr. Mario Fatala Chabén ANLIS Carlos G. Malbrán, Buenos Aires, Argentina. jacbua@yahoo.com
Fichera
L E
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Fuchs
A G
AG
Potenza
M
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Dubin
M
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Wenger
R O
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Moretti
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Scabone
C M
CM
Ruiz
A M
AM
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000633:Aminopyrine N-Demethylase / Q000187:drug effects; D000818:Animals; D014355:Chagas Disease / Q000188:drug therapy; D002522:Chlorocebus aethiops; D021983:Cyclophilins / Q000378:metabolism*; D003524:Cyclosporins / Q000494:pharmacology* / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019696:Peptidylprolyl Isomerase / Q000187:drug effects; D020112:Rhodamine 123 / Q000378:metabolism; D013997:Time Factors; D014344:Trypanocidal Agents / Q000494:pharmacology / Q000633:toxicity; D014349:Trypanosoma cruzi / Q000187:drug effects*; D020298:U937 Cells; D014709:Vero Cells
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D020112:Rhodamine 123; D000633:Aminopyrine N-Demethylase; D021983:Cyclophilins; D019696:Peptidylprolyl Isomerase