Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing
Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Medicine |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fmed.2019.00256/full |
| _version_ | 1828859541568094208 |
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| author | Chantal Reigada Chantal Reigada Melisa Sayé Melisa Sayé Otto Phanstiel Edward Valera-Vera Edward Valera-Vera Mariana R. Miranda Mariana R. Miranda Claudio A. Pereira Claudio A. Pereira |
| author_facet | Chantal Reigada Chantal Reigada Melisa Sayé Melisa Sayé Otto Phanstiel Edward Valera-Vera Edward Valera-Vera Mariana R. Miranda Mariana R. Miranda Claudio A. Pereira Claudio A. Pereira |
| author_sort | Chantal Reigada |
| collection | DOAJ |
| description | Trypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in T. cruzi. Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine, and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a high trypanocidal activity against T. cruzi amastigotes (IC50 values of 3.8, 1.9, and 2.9 μM, respectively) and trypomastigotes (IC50 values of 3.4, 2.7, and 1.3 μM, respectively) while in epimastigotes the IC50 were significantly higher (34.7, 41.4, and 39.7 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the T. cruzi polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation. |
| first_indexed | 2024-12-13T02:20:23Z |
| format | Article |
| id | doaj.art-6bb2ba388e5243ae9d06912e36271213 |
| institution | Directory Open Access Journal |
| issn | 2296-858X |
| language | English |
| last_indexed | 2024-12-13T02:20:23Z |
| publishDate | 2019-11-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Medicine |
| spelling | doaj.art-6bb2ba388e5243ae9d06912e362712132022-12-22T00:02:46ZengFrontiers Media S.A.Frontiers in Medicine2296-858X2019-11-01610.3389/fmed.2019.00256455308Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug RepurposingChantal Reigada0Chantal Reigada1Melisa Sayé2Melisa Sayé3Otto Phanstiel4Edward Valera-Vera5Edward Valera-Vera6Mariana R. Miranda7Mariana R. Miranda8Claudio A. Pereira9Claudio A. Pereira10Universidad de Buenos Aires, Facultad de Medicina, Instituto de Investigaciones Médicas A. Lanari, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Parasitología Molecular, Instituto de Investigaciones Médicas (IDIM), Universidad de Buenos Aires, Buenos Aires, ArgentinaUniversidad de Buenos Aires, Facultad de Medicina, Instituto de Investigaciones Médicas A. Lanari, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Parasitología Molecular, Instituto de Investigaciones Médicas (IDIM), Universidad de Buenos Aires, Buenos Aires, ArgentinaDepartment of Medical Education, University of Central Florida, Orlando, FL, United StatesUniversidad de Buenos Aires, Facultad de Medicina, Instituto de Investigaciones Médicas A. Lanari, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Parasitología Molecular, Instituto de Investigaciones Médicas (IDIM), Universidad de Buenos Aires, Buenos Aires, ArgentinaUniversidad de Buenos Aires, Facultad de Medicina, Instituto de Investigaciones Médicas A. Lanari, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Parasitología Molecular, Instituto de Investigaciones Médicas (IDIM), Universidad de Buenos Aires, Buenos Aires, ArgentinaUniversidad de Buenos Aires, Facultad de Medicina, Instituto de Investigaciones Médicas A. Lanari, Buenos Aires, ArgentinaConsejo Nacional de Investigaciones Científicas y Técnicas, Laboratorio de Parasitología Molecular, Instituto de Investigaciones Médicas (IDIM), Universidad de Buenos Aires, Buenos Aires, ArgentinaTrypanosoma cruzi is the causative agent of Chagas disease, a parasitic infection endemic in Latin America. In T. cruzi the transport of polyamines is essential because this organism is unable to synthesize these compounds de novo. Therefore, the uptake of polyamines from the extracellular medium is critical for survival of the parasite. The anthracene-putrescine conjugate Ant4 was first designed as a polyamine transport probe in cancer cells. Ant4 was also found to inhibit the polyamine transport system and produced a strong trypanocidal effect in T. cruzi. Considering that Ant4 is not currently approved by the FDA, in this work we performed computer simulations to find trypanocidal drugs approved for use in humans that have structures and activities similar to Ant4. Through a similarity ligand-based virtual screening using Ant4 as reference molecule, four possible inhibitors of polyamine transport were found. Three of them, promazine, chlorpromazine, and clomipramine, showed to be effective inhibitors of putrescine uptake, and also revealed a high trypanocidal activity against T. cruzi amastigotes (IC50 values of 3.8, 1.9, and 2.9 μM, respectively) and trypomastigotes (IC50 values of 3.4, 2.7, and 1.3 μM, respectively) while in epimastigotes the IC50 were significantly higher (34.7, 41.4, and 39.7 μM, respectively). Finally, molecular docking simulations suggest that the interactions between the T. cruzi polyamine transporter TcPAT12 and all the identified inhibitors occur in the same region of the protein. However, this location is different from the site occupied by the natural substrates. The value of this effort is that repurposing known drugs in the treatment of other pathologies, especially neglected diseases such as Chagas disease, significantly decreases the time and economic cost of implementation.https://www.frontiersin.org/article/10.3389/fmed.2019.00256/fullTrypanosoma cruziChagas diseasepolyamine transportdrug repositioningtrypanocidal drugspolyamines |
| spellingShingle | Chantal Reigada Chantal Reigada Melisa Sayé Melisa Sayé Otto Phanstiel Edward Valera-Vera Edward Valera-Vera Mariana R. Miranda Mariana R. Miranda Claudio A. Pereira Claudio A. Pereira Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing Frontiers in Medicine Trypanosoma cruzi Chagas disease polyamine transport drug repositioning trypanocidal drugs polyamines |
| title | Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing |
| title_full | Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing |
| title_fullStr | Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing |
| title_full_unstemmed | Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing |
| title_short | Identification of Trypanosoma cruzi Polyamine Transport Inhibitors by Computational Drug Repurposing |
| title_sort | identification of trypanosoma cruzi polyamine transport inhibitors by computational drug repurposing |
| topic | Trypanosoma cruzi Chagas disease polyamine transport drug repositioning trypanocidal drugs polyamines |
| url | https://www.frontiersin.org/article/10.3389/fmed.2019.00256/full |
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