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Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release

Nematode parasites of humans, livestock and crops dramatically impact human health and welfare. Alarmingly, parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides that protect crops are facing increasing restrictions because of poor phylogen...

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Autores principales: Harrington, Sean, Knox, Jessica J., Burns, Andrew R., Choo, Ken-Loon, Au, Aaron, Kitner, Megan, Haeberli, Cecile, Pyche, Jacob, D’Amata, Cassandra, Kim, Yong-Hyun, Volpatti, Jonathan R., Guiliani, Maximillano, Snider, Jamie, Wong, Victoria, Palmeira, Bruna M., Redman, Elizabeth M., Vaidya, Aditya S., Gilleard, John S., Stagljar, Igor, Cutler, Sean R., Kulke, Daniel, Dowling, James J., Yip, Christopher M., Keiser, Jennifer, Zasada, Inga, Lautens, Mark, Roy, Peter J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402605/
https://www.ncbi.nlm.nih.gov/pubmed/36002479
http://dx.doi.org/10.1038/s42003-022-03819-6
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author Harrington, Sean
Knox, Jessica J.
Burns, Andrew R.
Choo, Ken-Loon
Au, Aaron
Kitner, Megan
Haeberli, Cecile
Pyche, Jacob
D’Amata, Cassandra
Kim, Yong-Hyun
Volpatti, Jonathan R.
Guiliani, Maximillano
Snider, Jamie
Wong, Victoria
Palmeira, Bruna M.
Redman, Elizabeth M.
Vaidya, Aditya S.
Gilleard, John S.
Stagljar, Igor
Cutler, Sean R.
Kulke, Daniel
Dowling, James J.
Yip, Christopher M.
Keiser, Jennifer
Zasada, Inga
Lautens, Mark
Roy, Peter J.
author_facet Harrington, Sean
Knox, Jessica J.
Burns, Andrew R.
Choo, Ken-Loon
Au, Aaron
Kitner, Megan
Haeberli, Cecile
Pyche, Jacob
D’Amata, Cassandra
Kim, Yong-Hyun
Volpatti, Jonathan R.
Guiliani, Maximillano
Snider, Jamie
Wong, Victoria
Palmeira, Bruna M.
Redman, Elizabeth M.
Vaidya, Aditya S.
Gilleard, John S.
Stagljar, Igor
Cutler, Sean R.
Kulke, Daniel
Dowling, James J.
Yip, Christopher M.
Keiser, Jennifer
Zasada, Inga
Lautens, Mark
Roy, Peter J.
author_sort Harrington, Sean
collection PubMed
description Nematode parasites of humans, livestock and crops dramatically impact human health and welfare. Alarmingly, parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides that protect crops are facing increasing restrictions because of poor phylogenetic selectivity. Here, we exploit multiple motor outputs of the model nematode C. elegans towards nematicide discovery. This work yielded multiple compounds that selectively kill and/or immobilize diverse nematode parasites. We focus on one compound that induces violent convulsions and paralysis that we call nementin. We find that nementin stimulates neuronal dense core vesicle release, which in turn enhances cholinergic signaling. Consequently, nementin synergistically enhances the potency of widely-used non-selective acetylcholinesterase (AChE) inhibitors, but in a nematode-selective manner. Nementin therefore has the potential to reduce the environmental impact of toxic AChE inhibitors that are used to control nematode infections and infestations.
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spelling pubmed-94026052022-08-26 Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release Harrington, Sean Knox, Jessica J. Burns, Andrew R. Choo, Ken-Loon Au, Aaron Kitner, Megan Haeberli, Cecile Pyche, Jacob D’Amata, Cassandra Kim, Yong-Hyun Volpatti, Jonathan R. Guiliani, Maximillano Snider, Jamie Wong, Victoria Palmeira, Bruna M. Redman, Elizabeth M. Vaidya, Aditya S. Gilleard, John S. Stagljar, Igor Cutler, Sean R. Kulke, Daniel Dowling, James J. Yip, Christopher M. Keiser, Jennifer Zasada, Inga Lautens, Mark Roy, Peter J. Commun Biol Article Nematode parasites of humans, livestock and crops dramatically impact human health and welfare. Alarmingly, parasitic nematodes of animals have rapidly evolved resistance to anthelmintic drugs, and traditional nematicides that protect crops are facing increasing restrictions because of poor phylogenetic selectivity. Here, we exploit multiple motor outputs of the model nematode C. elegans towards nematicide discovery. This work yielded multiple compounds that selectively kill and/or immobilize diverse nematode parasites. We focus on one compound that induces violent convulsions and paralysis that we call nementin. We find that nementin stimulates neuronal dense core vesicle release, which in turn enhances cholinergic signaling. Consequently, nementin synergistically enhances the potency of widely-used non-selective acetylcholinesterase (AChE) inhibitors, but in a nematode-selective manner. Nementin therefore has the potential to reduce the environmental impact of toxic AChE inhibitors that are used to control nematode infections and infestations. Nature Publishing Group UK 2022-08-24 /pmc/articles/PMC9402605/ /pubmed/36002479 http://dx.doi.org/10.1038/s42003-022-03819-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Harrington, Sean
Knox, Jessica J.
Burns, Andrew R.
Choo, Ken-Loon
Au, Aaron
Kitner, Megan
Haeberli, Cecile
Pyche, Jacob
D’Amata, Cassandra
Kim, Yong-Hyun
Volpatti, Jonathan R.
Guiliani, Maximillano
Snider, Jamie
Wong, Victoria
Palmeira, Bruna M.
Redman, Elizabeth M.
Vaidya, Aditya S.
Gilleard, John S.
Stagljar, Igor
Cutler, Sean R.
Kulke, Daniel
Dowling, James J.
Yip, Christopher M.
Keiser, Jennifer
Zasada, Inga
Lautens, Mark
Roy, Peter J.
Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release
title Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release
title_full Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release
title_fullStr Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release
title_full_unstemmed Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release
title_short Egg-laying and locomotory screens with C. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release
title_sort egg-laying and locomotory screens with c. elegans yield a nematode-selective small molecule stimulator of neurotransmitter release
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9402605/
https://www.ncbi.nlm.nih.gov/pubmed/36002479
http://dx.doi.org/10.1038/s42003-022-03819-6
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