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...
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Format: | Article |
Language: | English |
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Frontiers Media S.A.
2021-09-01
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Series: | Frontiers in Endocrinology |
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Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2021.718363/full |
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doaj-8a21f17362a64b8da5c79e86ac91e8cd |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Louise E. Atkinson Ciaran J. McCoy Bethany A. Crooks Fiona M. McKay Paul McVeigh Darrin McKenzie Allister Irvine John Harrington Bruce A. Rosa Bruce A. Rosa Makedonka Mitreva Makedonka Mitreva Nikki J. Marks Aaron G. Maule Angela Mousley |
spellingShingle |
Louise E. Atkinson Ciaran J. McCoy Bethany A. Crooks Fiona M. McKay Paul McVeigh Darrin McKenzie Allister Irvine John Harrington Bruce A. Rosa Bruce A. Rosa Makedonka Mitreva Makedonka Mitreva Nikki J. Marks Aaron G. Maule Angela Mousley Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control Frontiers in Endocrinology neuropeptide G-protein coupled receptor FMRF-amide like peptide drug target nematode parasite |
author_facet |
Louise E. Atkinson Ciaran J. McCoy Bethany A. Crooks Fiona M. McKay Paul McVeigh Darrin McKenzie Allister Irvine John Harrington Bruce A. Rosa Bruce A. Rosa Makedonka Mitreva Makedonka Mitreva Nikki J. Marks Aaron G. Maule Angela Mousley |
author_sort |
Louise E. Atkinson |
title |
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_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_sort |
phylum-spanning neuropeptide gpcr identification and prioritization: shaping drug target discovery pipelines for nematode parasite control |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Endocrinology |
issn |
1664-2392 |
publishDate |
2021-09-01 |
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. |
topic |
neuropeptide G-protein coupled receptor FMRF-amide like peptide drug target nematode parasite |
url |
https://www.frontiersin.org/articles/10.3389/fendo.2021.718363/full |
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doaj-8a21f17362a64b8da5c79e86ac91e8cd2021-09-30T08:43:11ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922021-09-011210.3389/fendo.2021.718363718363Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite ControlLouise E. Atkinson0Ciaran J. McCoy1Bethany A. Crooks2Fiona M. McKay3Paul McVeigh4Darrin McKenzie5Allister Irvine6John Harrington7Bruce A. Rosa8Bruce A. Rosa9Makedonka Mitreva10Makedonka Mitreva11Nikki J. Marks12Aaron G. Maule13Angela Mousley14Microbes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomBoehringer Ingelheim Animal Health, Athens, GA, United StatesDivision of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United StatesMcDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United StatesDivision of Infectious Diseases, Department of Medicine, Washington University School of Medicine, St. Louis, MO, United StatesMcDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United StatesMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomMicrobes and Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen’s University Belfast, Belfast, United KingdomNematode 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.https://www.frontiersin.org/articles/10.3389/fendo.2021.718363/fullneuropeptideG-protein coupled receptorFMRF-amide like peptidedrug targetnematode parasite |