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Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.

ABSTRACT: Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays to find drugs able to inhibit TcPAT12, the only polyamine transporter described in T. cruzi. After a screening of 3000 FDA-approved drugs, 7 retinoids with medical use were retrieved and used for molecular docking assays with TcPAT12. From the docked molecules, isotretinoin, a well-known drug used for acne treatment, showed the best interaction score with TcPAT12 and was selected for further in vitro studies. Isotretinoin inhibited the polyamine transport, as well as other amino acid transporters from the same protein family (TcAAAP), with calculated IC50 values in the range of 4.6-10.3 ?M. It also showed a strong inhibition of trypomastigote burst from infected cells, with calculated IC50 of 130 nM (SI = 920) being significantly less effective on the epimastigote stage (IC50 = 30.6 ?M). The effect of isotretinoin on the parasites plasma membrane permeability and on mammalian cell viability was tested, and no change was observed. Autophagosomes and apoptotic bodies were detected as part of the mechanisms of isotretinoin-induced death indicating that the inhibition of transporters by isotretinoin causes nutrient starvation that triggers autophagic and apoptotic processes. In conclusion, isotretinoin is a promising trypanocidal drug since it is a multi-target inhibitor of essential metabolites transporters, in addition to being an FDA-approved drug largely used in humans, which could reduce significantly the requirements for its possible application in the treatment of Chagas disease.

SUBMITTER: Reigada C

PROVIDER: S-EPMC5371382 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.

Reigada Chantal C Valera-Vera Edward A EA Sayé Melisa M Errasti Andrea E AE Avila Carla C CC Miranda Mariana R MR Pereira Claudio A CA

PLoS neglected tropical diseases 20170317 3

Polyamines are essential compounds to all living organisms and in the specific case of Trypanosoma cruzi, the causative agent of Chagas disease, they are exclusively obtained through transport processes since this parasite is auxotrophic for polyamines. Previous works reported that retinol acetate inhibits Leishmania growth and decreases its intracellular polyamine concentration. The present work describes a combined strategy of drug repositioning by virtual screening followed by in vitro assays ...[more]

PMID: 28306713

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Project description:Several antigens from Trypanosoma cruzi, the causative agent of Chagas disease (CD), contain amino acid repeats identified as targets of the host immune response. Ribosomal proteins containing an Ala, Lys, Pro-rich repeat domain are among the T. cruzi antigens that are strongly recognized by antibodies from CD patients. Here we investigated the role of amino acid repeats present in the T. cruzi ribosomal protein L7a, by immunizing mice with recombinant versions of the full-length protein (TcRpL7a), as well as with truncated versions containing only the repetitive (TcRpL7aRep) or the non-repetitive domains (TcRpL7a?Rep). Mice immunized with full-length TcRpL7a produced high levels of IgG antibodies against the complete protein as well as against the repeat domain, whereas mice immunized with TcRpL7a?Rep or TcRpL7aRep produced very low levels or did not produce IgG antibodies against this antigen. Also in contrast to mice immunized with the full-length TcRpL7a, which produced high levels of IFN-?, only low levels of IFN-? or no IFN-? were detected in cultures of splenocytes derived from mice immunized with truncated versions of the protein. After challenging with trypomastigotes, mice immunized with the TcRpL7a were partially protected against the infection whereas immunization with TcRpL7a?Rep did not alter parasitemia levels compared to controls. Strikingly, mice immunized with TcRpL7aRep displayed an exacerbated parasitemia compared to the other groups and 100% mortality after infection. Analyses of antibody production in mice that were immunized with TcRpL7aRep prior to infection showed a reduced humoral response to parasite antigens as well as against an heterologous antigen. In vitro proliferation assays with mice splenocytes incubated with different mitogens in the presence of TcRpL7aRep resulted in a drastic inhibition of B-cell proliferation and antibody production. Taken together, these results indicate that the repeat domain of TcRpL7a acts as an immunosuppressive factor that down regulates the host B-cell response against parasite antigens favoring parasite multiplication in the mammalian host.

Dataset Information

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.

Publications

Trypanocidal Effect of Isotretinoin through the Inhibition of Polyamine and Amino Acid Transporters in Trypanosoma cruzi.

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