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Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development

Nematode parasites have a profound impact on humankind, infecting nearly one-quarter of the world’s population, as well as livestock. There is a pressing need for discovering nematicides due to the spread of resistance to currently used drugs. The free-living nematode Caenorhabditis elegans is a for...

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Autores principales: Risi, Gastón, Aguilera, Elena, Ladós, Enrique, Suárez, Gonzalo, Carrera, Inés, Álvarez, Guzmán, Salinas, Gustavo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466232/
https://www.ncbi.nlm.nih.gov/pubmed/30884899
http://dx.doi.org/10.3390/vetsci6010029
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author Risi, Gastón
Aguilera, Elena
Ladós, Enrique
Suárez, Gonzalo
Carrera, Inés
Álvarez, Guzmán
Salinas, Gustavo
author_facet Risi, Gastón
Aguilera, Elena
Ladós, Enrique
Suárez, Gonzalo
Carrera, Inés
Álvarez, Guzmán
Salinas, Gustavo
author_sort Risi, Gastón
collection PubMed
description Nematode parasites have a profound impact on humankind, infecting nearly one-quarter of the world’s population, as well as livestock. There is a pressing need for discovering nematicides due to the spread of resistance to currently used drugs. The free-living nematode Caenorhabditis elegans is a formidable experimentally tractable model organism that offers key advantages in accelerating nematicide discovery. We report the screening of drug-like libraries using an overnight high-throughput C. elegans assay, based on an automated infrared motility reader. As a proof of concept, we screened the “Pathogen Box” library, and identical results to a previous screen using Haemonchus contortus were obtained. We then screened an in-house library containing a diversity of compound families. Most active compounds had a conjugation of an unsaturation with an electronegative atom (N, O, or S) and an aromatic ring. Importantly, we identified symmetric arylidene ketones and aryl hydrazine derivatives as novel nematicides. Furthermore, one of these compounds, (1E,2E)-1,2-bis(thiophen-3-ylmethylene)hydrazine, was active as a nematicide at 25 µm, but innocuous to the vertebrate model zebrafish at 50 µm. Our results identified novel nematicidal scaffolds and illustrate the value of C. elegans in accelerating nematicide discovery using a nonlabor-intensive automated assay that provides a simple overnight readout.
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spelling pubmed-64662322019-04-19 Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development Risi, Gastón Aguilera, Elena Ladós, Enrique Suárez, Gonzalo Carrera, Inés Álvarez, Guzmán Salinas, Gustavo Vet Sci Article Nematode parasites have a profound impact on humankind, infecting nearly one-quarter of the world’s population, as well as livestock. There is a pressing need for discovering nematicides due to the spread of resistance to currently used drugs. The free-living nematode Caenorhabditis elegans is a formidable experimentally tractable model organism that offers key advantages in accelerating nematicide discovery. We report the screening of drug-like libraries using an overnight high-throughput C. elegans assay, based on an automated infrared motility reader. As a proof of concept, we screened the “Pathogen Box” library, and identical results to a previous screen using Haemonchus contortus were obtained. We then screened an in-house library containing a diversity of compound families. Most active compounds had a conjugation of an unsaturation with an electronegative atom (N, O, or S) and an aromatic ring. Importantly, we identified symmetric arylidene ketones and aryl hydrazine derivatives as novel nematicides. Furthermore, one of these compounds, (1E,2E)-1,2-bis(thiophen-3-ylmethylene)hydrazine, was active as a nematicide at 25 µm, but innocuous to the vertebrate model zebrafish at 50 µm. Our results identified novel nematicidal scaffolds and illustrate the value of C. elegans in accelerating nematicide discovery using a nonlabor-intensive automated assay that provides a simple overnight readout. MDPI 2019-03-17 /pmc/articles/PMC6466232/ /pubmed/30884899 http://dx.doi.org/10.3390/vetsci6010029 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Risi, Gastón
Aguilera, Elena
Ladós, Enrique
Suárez, Gonzalo
Carrera, Inés
Álvarez, Guzmán
Salinas, Gustavo
Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development
title Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development
title_full Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development
title_fullStr Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development
title_full_unstemmed Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development
title_short Caenorhabditis elegans Infrared-Based Motility Assay Identified New Hits for Nematicide Drug Development
title_sort caenorhabditis elegans infrared-based motility assay identified new hits for nematicide drug development
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6466232/
https://www.ncbi.nlm.nih.gov/pubmed/30884899
http://dx.doi.org/10.3390/vetsci6010029
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