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Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control
Nematode parasites undermine human health and global food security. The frontline anthelmintic portfolio used to treat parasitic nematodes is threatened by the escalation of anthelmintic resistance, resulting in a demand for new drug targets for parasite control. Nematode neuropeptide signalling pat...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515059/ https://www.ncbi.nlm.nih.gov/pubmed/34659113 http://dx.doi.org/10.3389/fendo.2021.718363 |
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author | Atkinson, Louise E. McCoy, Ciaran J. Crooks, Bethany A. McKay, Fiona M. McVeigh, Paul McKenzie, Darrin Irvine, Allister Harrington, John Rosa, Bruce A. Mitreva, Makedonka Marks, Nikki J. Maule, Aaron G. Mousley, Angela |
author_facet | Atkinson, Louise E. McCoy, Ciaran J. Crooks, Bethany A. McKay, Fiona M. McVeigh, Paul McKenzie, Darrin Irvine, Allister Harrington, John Rosa, Bruce A. Mitreva, Makedonka Marks, Nikki J. Maule, Aaron G. Mousley, Angela |
author_sort | Atkinson, Louise E. |
collection | PubMed |
description | Nematode parasites undermine human health and global food security. The frontline anthelmintic portfolio used to treat parasitic nematodes is threatened by the escalation of anthelmintic resistance, resulting in a demand for new drug targets for parasite control. Nematode neuropeptide signalling pathways represent an attractive source of novel drug targets which currently remain unexploited. The complexity of the nematode neuropeptidergic system challenges the discovery of new targets for parasite control, however recent advances in parasite ‘omics’ offers an opportunity for the in silico identification and prioritization of targets to seed anthelmintic discovery pipelines. In this study we employed Hidden Markov Model-based searches to identify ~1059 Caenorhabditis elegans neuropeptide G-protein coupled receptor (Ce-NP-GPCR) encoding gene homologs in the predicted protein datasets of 10 key parasitic nematodes that span several phylogenetic clades and lifestyles. We show that, whilst parasitic nematodes possess a reduced complement of Ce-NP-GPCRs, several receptors are broadly conserved across nematode species. To prioritize the most appealing parasitic nematode NP-GPCR anthelmintic targets, we developed a novel in silico nematode parasite drug target prioritization pipeline that incorporates pan-phylum NP-GPCR conservation, C. elegans-derived reverse genetics phenotype, and parasite life-stage specific expression datasets. Several NP-GPCRs emerge as the most attractive anthelmintic targets for broad spectrum nematode parasite control. Our analyses have also identified the most appropriate targets for species- and life stage- directed chemotherapies; in this context we have identified several NP-GPCRs with macrofilaricidal potential. These data focus functional validation efforts towards the most appealing NP-GPCR targets and, in addition, the prioritization strategy employed here provides a blueprint for parasitic nematode target selection beyond NP-GPCRs. |
format | Online Article Text |
id | pubmed-8515059 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-85150592021-10-15 Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control Atkinson, Louise E. McCoy, Ciaran J. Crooks, Bethany A. McKay, Fiona M. McVeigh, Paul McKenzie, Darrin Irvine, Allister Harrington, John Rosa, Bruce A. Mitreva, Makedonka Marks, Nikki J. Maule, Aaron G. Mousley, Angela Front Endocrinol (Lausanne) Endocrinology Nematode parasites undermine human health and global food security. The frontline anthelmintic portfolio used to treat parasitic nematodes is threatened by the escalation of anthelmintic resistance, resulting in a demand for new drug targets for parasite control. Nematode neuropeptide signalling pathways represent an attractive source of novel drug targets which currently remain unexploited. The complexity of the nematode neuropeptidergic system challenges the discovery of new targets for parasite control, however recent advances in parasite ‘omics’ offers an opportunity for the in silico identification and prioritization of targets to seed anthelmintic discovery pipelines. In this study we employed Hidden Markov Model-based searches to identify ~1059 Caenorhabditis elegans neuropeptide G-protein coupled receptor (Ce-NP-GPCR) encoding gene homologs in the predicted protein datasets of 10 key parasitic nematodes that span several phylogenetic clades and lifestyles. We show that, whilst parasitic nematodes possess a reduced complement of Ce-NP-GPCRs, several receptors are broadly conserved across nematode species. To prioritize the most appealing parasitic nematode NP-GPCR anthelmintic targets, we developed a novel in silico nematode parasite drug target prioritization pipeline that incorporates pan-phylum NP-GPCR conservation, C. elegans-derived reverse genetics phenotype, and parasite life-stage specific expression datasets. Several NP-GPCRs emerge as the most attractive anthelmintic targets for broad spectrum nematode parasite control. Our analyses have also identified the most appropriate targets for species- and life stage- directed chemotherapies; in this context we have identified several NP-GPCRs with macrofilaricidal potential. These data focus functional validation efforts towards the most appealing NP-GPCR targets and, in addition, the prioritization strategy employed here provides a blueprint for parasitic nematode target selection beyond NP-GPCRs. Frontiers Media S.A. 2021-09-30 /pmc/articles/PMC8515059/ /pubmed/34659113 http://dx.doi.org/10.3389/fendo.2021.718363 Text en Copyright © 2021 Atkinson, McCoy, Crooks, McKay, McVeigh, McKenzie, Irvine, Harrington, Rosa, Mitreva, Marks, Maule and Mousley https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Endocrinology Atkinson, Louise E. McCoy, Ciaran J. Crooks, Bethany A. McKay, Fiona M. McVeigh, Paul McKenzie, Darrin Irvine, Allister Harrington, John Rosa, Bruce A. Mitreva, Makedonka Marks, Nikki J. Maule, Aaron G. Mousley, Angela Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control |
title | Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control |
title_full | Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control |
title_fullStr | Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control |
title_full_unstemmed | Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control |
title_short | Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control |
title_sort | phylum-spanning neuropeptide gpcr identification and prioritization: shaping drug target discovery pipelines for nematode parasite control |
topic | Endocrinology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8515059/ https://www.ncbi.nlm.nih.gov/pubmed/34659113 http://dx.doi.org/10.3389/fendo.2021.718363 |
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