Anti-parasitic activity of Ciclosporin A and some non-immunosuppresive derivatives on Trypanosoma cruzi

POTENZA, MARIANA.; BÚA, J.; FICHERA, L.; AINCIART, N.;RUIZ

Córdoba, Argentina

Congreso; XXXVIII Reunión Anual de la Sociedad Argentina de Bioquímica y Biología Molecular.; 2002

Sociedad Argentina de Bioquímica y Biología Molecular

Cyclosporin A (CsA) is an anti-parasiticidal agent with immunosuppressive effects exerted by the binding to cyclophilins (CyPs), proteins that  mediate protein folding events. We cloned several CyPs isoforms from T. cruzi and demonstrated that TcCyP19 protein, exhibited enzymatic activity inhibited by CsA. Non- immunosuppressive CsA analogs  have also shown anti-parasitic activity  in other parasites. Here we show the trypanocidal activity of CsA and some analogs on T. cruzi. Inhibition of epimastigotes growth was performed with CsA and derivatives on T. cruzi CL Brener clone. CsA showed an IC50 of 6.6 mM. Four drugs showed lower IC50 than CsA, H-7-94, F-7-62, A-4-16, and E-6-44, with an IC50 of 0.6, 4.4, 4.8 and 6.3 mM, respectively. Other analogs were not as effective as CsA, like D-6-45 (8.9mM), C-5-34 (12.6mM) and SDZ 211-810 (13.8 mM). Effects on trypomastigotes lysis showed an IC50 of  14.1 mM for CsA. Again, the analogs H-7-94, F-7-62, A-4-16 and E-6-44 showed lower IC50 being 3.9, 6.3, 6.9 and 12.3 mM respectively. Finally, analogs H-7-94, F-7-62 and A-4-16 were not toxic on mammalian cells at 50 M concentration. These results confirm the anti-parasitic activity of CsA derivatives. We will determine the mechanism of action of CsA as trypanocidal drug testing if CsA analogs bind CyPs proteins or if other target molecules are involved.