Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control.

Louise E Atkinson,Bethany A Crooks,Makedonka Mitreva,Nikki J Marks,Bruce A Rosa,Angela Mousley,Aaron G Maule,John Harrington,Allister Irvine,Paul Mcveigh,Fiona M Mckay,Ciaran J Mccoy,Darrin Mckenzie

doi:10.3389/fendo.2021.718363

Abstract

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.

Highlights

Nematode parasites continue to have a global impact on human health and agricultural productivity such that novel mode-ofaction anthelmintics are critical for sustained parasite control, especially in light of the escalation in anthelmintic resistance [1,2,3]
In this study we identified 1059 putative Ce-NP-GPCR homologs in the predicted protein datasets of 10 phylogenetically dispersed nematode parasites
Several key points emerge from this study: Nematode Parasites Possess a Reduced Complement of Caenorhabditis elegans NP-GPCR Homologs All 10 parasitic nematodes examined in this study exhibited restricted profiles of the 152 Ce-NP-GPCRs [21-78% Ce-NPGPCR profile; see Supplementary Table 2, Supplementary Data Sheet 1 and Figure 2] this trend is similar to that noted previously [35, 36]

Summary

Introduction

Nematode parasites continue to have a global impact on human health and agricultural productivity such that novel mode-ofaction anthelmintics are critical for sustained parasite control, especially in light of the escalation in anthelmintic resistance [1,2,3]. Whilst the nematode neuromuscular system is a proven drug target, it remains underexploited [4, 5]. The majority of frontline anthelmintics only target aspects of neuromuscular signaling controlled by ion channels, the neuropeptide signaling system is critical to normal nematode neuromuscular function [6, 7]. NP-GPCRs have yet to be exploited for chemotherapeutic control of nematode parasites. In part, this is due to limited knowledge of NP-GPCR profiles in key parasitic nematode species which would enable NP-GPCR target prioritization

Methods

Results

Conclusion