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Endocrinol."],"abstract":"<jats:p>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 \u2018omics\u2019 offers an opportunity for the <jats:italic>in silico<\/jats:italic> identification and prioritization of targets to seed anthelmintic discovery pipelines. In this study we employed Hidden Markov Model-based searches to identify ~1059 <jats:italic>Caenorhabditis elegans<\/jats:italic> neuropeptide G-protein coupled receptor (<jats:italic>Ce-NP-GPCR<\/jats:italic>) 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 <jats:italic>Ce-NP-GPCRs<\/jats:italic>, several receptors are broadly conserved across nematode species. To prioritize the most appealing parasitic nematode NP-GPCR anthelmintic targets, we developed a novel <jats:italic>in silico<\/jats:italic> nematode parasite drug target prioritization pipeline that incorporates pan-phylum <jats:italic>NP-GPCR<\/jats:italic> conservation, <jats:italic>C. elegans-<\/jats:italic>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 <jats:italic>NP-GPCRs<\/jats:italic> 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.<\/jats:p>","DOI":"10.3389\/fendo.2021.718363","type":"journal-article","created":{"date-parts":[[2021,9,30]],"date-time":"2021-09-30T20:35:19Z","timestamp":1633034119000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control"],"prefix":"10.3389","volume":"12","author":[{"given":"Louise E.","family":"Atkinson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ciaran J.","family":"McCoy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany A.","family":"Crooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona M.","family":"McKay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"McVeigh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darrin","family":"McKenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allister","family":"Irvine","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Harrington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bruce A.","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makedonka","family":"Mitreva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nikki J.","family":"Marks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaron G.","family":"Maule","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Mousley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,9,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/mpp.12057","article-title":"Top 10 Plant-Parasitic Nematodes in Molecular Plant Pathology","volume":"14","author":"Jones","year":"2013","journal-title":"Mol Plant Pathol"},{"key":"B2","doi-asserted-by":"crossref","DOI":"10.1016\/B978-0-323-55512-8.00027-2","article-title":"Neglected Tropical Diseases: Public Health Control Programs and Mass Drug Administration","volume-title":"Hunter\u2019s Tropical Medicine and Emerging Infectious Diseases","author":"Hotez","year":"2020"},{"key":"B3","doi-asserted-by":"publisher","first-page":"105103","DOI":"10.1016\/j.prevetmed.2020.105103","article-title":"Initial Assessment of the Economic Burden of Major Parasitic Helminth Infections to the Ruminant Livestock Industry in Europe","volume":"182","author":"Charlier","year":"2020","journal-title":"Prev Vet Med"},{"key":"B4","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1016\/j.ijpddr.2011.09.003","article-title":"Ion Channels and Receptor as Targets for the Control of Parasitic Nematodes","volume":"1","author":"Wolstenholme","year":"2011","journal-title":"Int J Parasitol: Drugs Drug Resist"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4419-6902-6_7","article-title":"Control of Nematode Parasites With Agents Acting on Neuro-Musculature Systems: Lessons for Neuropeptide Ligand Discovery","volume":"692","author":"Martin","year":"2010","journal-title":"Neuropeptide Syst as Targets Parasite Pest Control"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2006.06.010","article-title":"The FLP-Side of Nematodes","volume":"22","author":"McVeigh","year":"2006","journal-title":"Trends Parasitol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2012.00167","article-title":"Neuropeptide GPCRs in C. 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