Zebrafish toxicological screening could aid Leishmaniosis drug discovery

Hirla Costa Silva Fukushima,Princia Grejo Setti,Luís Kluwe De Aguiar,Ricardo Lacava Bailone,Ricardo Carneiro Borra,Helena Janke,Tatiana Corrêa

doi:10.1186/s42826-021-00104-1

Hirla Costa Silva Fukushima, Princia Grejo Setti + Show 5 more

Open Access

https://doi.org/10.1186/s42826-021-00104-1

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Abstract

BackgroundRecently 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).ResultsTests 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.ConclusionsResults using Pltf-AcHpNrCd with zebrafish reproduced that found in the toxicological tests with mammals to a portion of the costs and time of experimentation.

Highlights

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
Currently, the tests used in toxicological screening are costly, time-consuming, and not satisfactorily predictive, toxicity is one of the major attritions causes during the drug development process
At concentrations of 6.25 and 12.5 μM, the embryos remained alive for 96 h of evaluation, but most embryos exposed to 12.5 μM did not hatch, presented yolk sac hemorrhages and bradycardia (Fig. 4), which Median effective concentration (EC50)% 8.57 μM

Summary

Introduction

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. Zebrafish can bridge the gap between in vitro safety assays and mammals’ models in a fast and cost-effective manner and would have a key role in accelerating the process of new chemicals development, improving prediction, prioritizing safe compounds, and decreasing testing time and costs substantially [4,5,6]. This model has the advantage of having OECD-specific guidelines for safety evaluation of chemical compounds (acute toxicity), which is performed within 96 h [7]. The three main reasons behind the retirement of drugs in clinical phases and post market withdrawal could possibly have been predicted in embryo and larvae zebrafish trials in the early stages of development and saved mammals models (mice, rabbits, dogs, monkeys) and billions of dollars invested

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