Zebrafish toxicological screening could aid Leishmaniosis drug discovery
Abstract Background Recently a screen from a library of 1.8 million compounds identified in vitro a potent activity of the 2-aminobenzimidazoles series against Leishmania infantum, the etiological agent responsible by over 20.000 deaths each year. Several analogs were synthesized and in vitro tested...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2021-09-01
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| Series: | Laboratory Animal Research |
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| Online Access: | https://doi.org/10.1186/s42826-021-00104-1 |
| _version_ | 1818733276080111616 |
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| author | Hirla Costa Silva Fukushima Ricardo Lacava Bailone Tatiana Corrêa Helena Janke Luís Kluwe De Aguiar Princia Grejo Setti Ricardo Carneiro Borra |
| author_facet | Hirla Costa Silva Fukushima Ricardo Lacava Bailone Tatiana Corrêa Helena Janke Luís Kluwe De Aguiar Princia Grejo Setti Ricardo Carneiro Borra |
| author_sort | Hirla Costa Silva Fukushima |
| collection | DOAJ |
| description | Abstract Background Recently a screen from a library of 1.8 million compounds identified in vitro a potent activity of the 2-aminobenzimidazoles series against Leishmania infantum, the etiological agent responsible by over 20.000 deaths each year. Several analogs were synthesized and in vitro tested through an optimization program, leading to a promising 2-aminobenzimidazoles derived compound (2amnbzl-d) that was progressed to in vivo mice studies. However, the not expected toxic effects prevented its progression to more advanced preclinical and clinical phases of drug development. Due to limitations of cell models in detecting whole organism complex interactions, 90% of the compounds submitted to pre-clinical tests are reproved. The use of Zebrafish embryo models could improve this rate, saving mammals, time and costs in the development of new drugs. To test this hypothesis, we compared 2amnbzl-d with two compounds with already established safety profile: carbamazepine and benznidazole, using an embryo Zebrafish platform based on acute toxicity, hepatotoxicity, neurotoxicity and cardiotoxicity assays (Pltf-AcHpNrCd). Results Tests were performed blindly, and the results demonstrated the presence of lethal and teratogenic effects (CL50%: 14.8 µM; EC50%: 8.6 µM), hepatotoxic in concentrations above 7.5 µM and neurotoxic in embryos exposed to 15 µM of 2amnbzl-d. Nevertheless, benznidazole exposition showed no toxicity and only the 100 µM of carbamazepine induced a bradycardia. Conclusions Results using Pltf-AcHpNrCd with zebrafish reproduced that found in the toxicological tests with mammals to a portion of the costs and time of experimentation. |
| first_indexed | 2024-12-17T23:46:53Z |
| format | Article |
| id | doaj.art-db513b5f5eb04d04a853b12119534ac6 |
| institution | Directory Open Access Journal |
| issn | 2233-7660 |
| language | English |
| last_indexed | 2024-12-17T23:46:53Z |
| publishDate | 2021-09-01 |
| publisher | BMC |
| record_format | Article |
| series | Laboratory Animal Research |
| spelling | doaj.art-db513b5f5eb04d04a853b12119534ac62022-12-21T21:28:18ZengBMCLaboratory Animal Research2233-76602021-09-0137111110.1186/s42826-021-00104-1Zebrafish toxicological screening could aid Leishmaniosis drug discoveryHirla Costa Silva Fukushima0Ricardo Lacava Bailone1Tatiana Corrêa2Helena Janke3Luís Kluwe De Aguiar4Princia Grejo Setti5Ricardo Carneiro Borra6Center of Biological and Health Sciences, Federal University of Sao CarlosDepartment of Federal Inspection Service, Ministry of Agriculture, Livestock and Supply of Brazil, Federal Inspection Service,Department of Genetic and Evolution, Federal University of São CarlosDepartment of Genetic and Evolution, Federal University of São CarlosDepartment of Food Technology and Innovation, Harper Adams UniversityDepartment of Genetic and Evolution, Federal University of São CarlosDepartment of Genetic and Evolution, Federal University of São CarlosAbstract Background Recently a screen from a library of 1.8 million compounds identified in vitro a potent activity of the 2-aminobenzimidazoles series against Leishmania infantum, the etiological agent responsible by over 20.000 deaths each year. Several analogs were synthesized and in vitro tested through an optimization program, leading to a promising 2-aminobenzimidazoles derived compound (2amnbzl-d) that was progressed to in vivo mice studies. However, the not expected toxic effects prevented its progression to more advanced preclinical and clinical phases of drug development. Due to limitations of cell models in detecting whole organism complex interactions, 90% of the compounds submitted to pre-clinical tests are reproved. The use of Zebrafish embryo models could improve this rate, saving mammals, time and costs in the development of new drugs. To test this hypothesis, we compared 2amnbzl-d with two compounds with already established safety profile: carbamazepine and benznidazole, using an embryo Zebrafish platform based on acute toxicity, hepatotoxicity, neurotoxicity and cardiotoxicity assays (Pltf-AcHpNrCd). Results Tests were performed blindly, and the results demonstrated the presence of lethal and teratogenic effects (CL50%: 14.8 µM; EC50%: 8.6 µM), hepatotoxic in concentrations above 7.5 µM and neurotoxic in embryos exposed to 15 µM of 2amnbzl-d. Nevertheless, benznidazole exposition showed no toxicity and only the 100 µM of carbamazepine induced a bradycardia. Conclusions Results using Pltf-AcHpNrCd with zebrafish reproduced that found in the toxicological tests with mammals to a portion of the costs and time of experimentation.https://doi.org/10.1186/s42826-021-00104-13RsAnimal healthHuman healthImmunityLeishmanioseToxicology |
| spellingShingle | Hirla Costa Silva Fukushima Ricardo Lacava Bailone Tatiana Corrêa Helena Janke Luís Kluwe De Aguiar Princia Grejo Setti Ricardo Carneiro Borra Zebrafish toxicological screening could aid Leishmaniosis drug discovery Laboratory Animal Research 3Rs Animal health Human health Immunity Leishmaniose Toxicology |
| title | Zebrafish toxicological screening could aid Leishmaniosis drug discovery |
| title_full | Zebrafish toxicological screening could aid Leishmaniosis drug discovery |
| title_fullStr | Zebrafish toxicological screening could aid Leishmaniosis drug discovery |
| title_full_unstemmed | Zebrafish toxicological screening could aid Leishmaniosis drug discovery |
| title_short | Zebrafish toxicological screening could aid Leishmaniosis drug discovery |
| title_sort | zebrafish toxicological screening could aid leishmaniosis drug discovery |
| topic | 3Rs Animal health Human health Immunity Leishmaniose Toxicology |
| url | https://doi.org/10.1186/s42826-021-00104-1 |
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