Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control.
Phylum-Spanning Neuropeptide GPCR Identification and Prioritization: Shaping Drug Target Discovery Pipelines for Nematode Parasite Control.
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跨门神经肽 GPCR 识别和优先排序：塑造线虫寄生虫控制的药物靶点发现管道。
DOI：
10.3389/fendo.2021.718363
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发表时间：
2021
影响因子：
5.2
通讯作者：
Mousley A
中科院分区：
文献类型：
--
作者：
Atkinson LE;McCoy CJ;Crooks BA;McKay FM;McVeigh P;McKenzie D;Irvine A;Harrington J;Rosa BA;Mitreva M;Marks NJ;Maule AG;Mousley A
线虫寄生虫危害人类健康和全球粮食安全。用于治疗寄生线虫的一线驱虫药组合受到驱虫药耐药性升级的威胁，导致对用于寄生虫控制的新药靶点的需求。线虫神经肽信号通路是目前尚未开发的新型药物靶点的一个有吸引力的来源。线虫神经肽能系统的复杂性挑战了寄生虫控制的新靶标的发现，然而寄生虫“组学”的最新进展提供了一个机会，用于在计算机上识别和优先排序靶标，以种子驱虫剂发现管道。在这项研究中，我们采用隐马尔可夫模型为基础的搜索，以确定~1059秀丽隐杆线虫神经肽G蛋白偶联受体（Ce-NP-GPCR）编码基因同源物的预测蛋白质数据集的10个关键的寄生线虫，跨越几个系统发育分支和生活方式。我们表明，虽然寄生线虫具有减少的Ce-NP-GPCR的补充，几种受体广泛保守的线虫物种。为了优先考虑最有吸引力的寄生线虫NP-GPCR驱虫靶标，我们开发了一种新的计算机模拟线虫寄生虫药物靶标优先级排序管道，其结合了泛门NP-GPCR保守性，C. elegans衍生的反向遗传学表型和寄生虫生命阶段特异性表达数据集。几种NP-GPCR成为广谱线虫寄生虫控制的最有吸引力的驱虫靶标。我们的分析还确定了针对物种和生命阶段的化疗的最合适的靶点;在这种情况下，我们确定了几种具有杀巨丝状体潜力的NP-GPCR。这些数据将功能验证工作集中在最有吸引力的NP-GPCR靶标上，此外，本文采用的优先级排序策略为NP-GPCR之外的寄生线虫靶标选择提供了蓝图。
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.
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影响因子：
3.8
作者：
Ballesteros C;Tritten L;O'Neill M;Burkman E;Zaky WI;Xia J;Moorhead A;Williams SA;Geary TG
通讯作者：
Geary TG
影响因子：
3.1
作者：
Anderson, Alexandra;Chew, Yee Lian;McMullan, Rachel
通讯作者：
McMullan, Rachel
影响因子：
25
作者：
Barrios, Arantza;Ghosh, Rajarshi;Fang, Chunhui;Emmons, Scott W.;Barr, Maureen M.
通讯作者：
Barr, Maureen M.
影响因子：
5.3
作者：
Hapiak, Vera;Summers, Philip;Komuniecki, Richard
通讯作者：
Komuniecki, Richard
影响因子：
6.7
作者：
Hansen TVA;Cirera S;Neveu C;Courtot E;Charvet CL;Calloe K;Klaerke DA;Martin RJ
通讯作者：
Martin RJ