In vitro anti-parasitic activity of Cyclosporin A analogs on Trypanosoma cruzi

Búa, Jacqueline; Ruiz, Andrés M.; Potenza, Mariana; Fichera, Laura E.

doi:10.1016/j.bmcl.2004.07.003

Cited by 32 publications

(16 citation statements)

References 20 publications

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“…TcCaN inhibitor CsA affected epimastigote multiplication, confirming the data reported by Búa et al [59]. CsA probably binds to the cytosolic protein cyclophilin (CyP), forming a complex that, through its association with the invariant regulatory subunit TcCaNB, would inhibit TcCaN in a manner similar to that of its mammalian counterpart [60].…”

Section: Discussionsupporting

confidence: 87%

“…CsA probably binds to the cytosolic protein cyclophilin (CyP), forming a complex that, through its association with the invariant regulatory subunit TcCaNB, would inhibit TcCaN in a manner similar to that of its mammalian counterpart [60]. Members of the CyP family identified in T. cruzi , called peptidyl-prolyl cis/trans isomerases, have their activity inhibited by CsA and its analogs [59], and the affinity of CyP for CsA has been documented [61]. It appears that the involvement of TcCaNA2 in epimastigote proliferation is partial, as judged by the weak inhibitory effect on epimastigote replication following treatment with antisense oligonucleotides against TcCaNA2.…”

Section: Discussionmentioning

confidence: 99%

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A Cytoplasmic New Catalytic Subunit of Calcineurin in Trypanosoma cruzi and Its Molecular and Functional Characterization

et al. 2014

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Parasitological cure for Chagas disease is considered extremely difficult to achieve because of the lack of effective chemotherapeutic agents against Trypanosoma cruzi at different stages of infection. There are currently only two drugs available. These have several limitations and can produce serious side effects. Thus, new chemotherapeutic targets are much sought after. Among T. cruzi components involved in key processes such as parasite proliferation and host cell invasion, Ca2+-dependent molecules play an important role. Calcineurin (CaN) is one such molecule. In this study, we cloned a new isoform of the gene coding for CL strain catalytic subunit CaNA (TcCaNA2) and characterized it molecularly and functionally. There is one copy of the TcCaNA2 gene per haploid genome. It is constitutively transcribed in all T. cruzi developmental forms and is localized predominantly in the cytosol. In the parasite, TcCaNA2 is associated with CaNB. The recombinant protein TcCaNA2 has phosphatase activity that is enhanced by Mn2+/Ni2+. The participation of TcCaNA2 in target cell invasion by metacyclic trypomastigotes was also demonstrated. Metacyclic forms with reduced TcCaNA2 expression following treatment with morpholino antisense oligonucleotides targeted to TcCaNA2 invaded HeLa cells at a lower rate than control parasites treated with morpholino sense oligonucleotides. Similarly, the decreased expression of TcCaNA2 following treatment with antisense morpholino oligonucleotides partially affected the replication of epimastigotes, although to a lesser extent than the decrease in expression following treatment with calcineurin inhibitors. Our findings suggest that the calcineurin activities of TcCaNA2/CaNB and TcCaNA/CaNB, which have distinct cellular localizations (the cytoplasm and the nucleus, respectively), may play a critical role at different stages of T. cruzi development, the former in host cell invasion and the latter in parasite multiplication.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

A Cytoplasmic New Catalytic Subunit of Calcineurin in Trypanosoma cruzi and Its Molecular and Functional Characterization

et al. 2014

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“…It is worth noting that F-7-62 inhibition of rhodamine efflux at a concentration of 1 mg/ml exhibited a similar level of inhibition as CsA at 10 mg/ml. This feature has been observed before, when the F-7-62 and H-7-94 CsA analogues were tested on inhibition of T. cruzi epimastigote proliferation (Bú a et al 2004). In this experiment, higher concentrations of the F-7-62 derivative resulted in a massive dye efflux due to a lytic effect on the parasite.…”

Section: Controlsupporting

confidence: 73%

“…39 mM (Table 1). Results obtained with CsA, H-7-94 and F-7-62 have previously been published elsewhere (Bú a et al 2004) and were included in this table for comparison.…”

Section: Effect Of Csa Derivatives On T Cruzi In Vitromentioning

confidence: 99%

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

et al. 2007

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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.

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“…Phosphatase-Cyclophilin 19 is a peptidyl-prolyl isomerase that, like other cyclophilins, is inhibited by the immunosuppressant cyclosporine A (CsA) (27). Preincubation of Cyp19 with 20 nM CsA before trialysin addition in our in vitro assay inhibited Cyp19-trialysinmediated bio-energetic parasite activation, whereas 100 nM FIGURE 1.…”

Section: Cyclophilin 19-trialysin Bio-energetic Activation Of T Cruzmentioning

confidence: 99%

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

Kulkarni

Karafova

Kamysz

et al. 2013

Journal of Biological Chemistry

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Background:The mechanisms of insect immune peptide recognition and evasion by T. cruzi are unknown. Results: Secreted parasite cyclophilin neutralizes lytic peptide, causes activation of parasite calcineurin, and enhances parasite infection. Conclusion: Cyclophilin is a key mediator of antimicrobial peptide evasion and triggers parasite calcineurin signaling. Significance: The cyclophilin-calcineurin pathway is an extracellular peptide microbial-host sensing mechanism.

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In vitro anti-parasitic activity of Cyclosporin A analogs on Trypanosoma cruzi

Cited by 32 publications

References 20 publications

A Cytoplasmic New Catalytic Subunit of Calcineurin in Trypanosoma cruzi and Its Molecular and Functional Characterization

A Cytoplasmic New Catalytic Subunit of Calcineurin in Trypanosoma cruzi and Its Molecular and Functional Characterization

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

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

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