Institute of Organismic and Molecular Evolution (iomE), Anthropology, Johannes Gutenberg University Mainz, Mainz, Germany.
Present address: Institute for Virology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
BMC Genomics. 2022 Sep 30;23(1):677. doi: 10.1186/s12864-022-08882-1.
With the expansion of animal production, parasitic helminths are gaining increasing economic importance. However, application of several established deworming agents can harm treated hosts and environment due to their low specificity. Furthermore, the number of parasite strains showing resistance is growing, while hardly any new anthelminthics are being developed. Here, we present a bioinformatics workflow designed to reduce the time and cost in the development of new strategies against parasites. The workflow includes quantitative transcriptomics and proteomics, 3D structure modeling, binding site prediction, and virtual ligand screening. Its use is demonstrated for Acanthocephala (thorny-headed worms) which are an emerging pest in fish aquaculture. We included three acanthocephalans (Pomphorhynchus laevis, Neoechinorhynchus agilis, Neoechinorhynchus buttnerae) from four fish species (common barbel, European eel, thinlip mullet, tambaqui).
The workflow led to eleven highly specific candidate targets in acanthocephalans. The candidate targets showed constant and elevated transcript abundances across definitive and accidental hosts, suggestive of constitutive expression and functional importance. Hence, the impairment of the corresponding proteins should enable specific and effective killing of acanthocephalans. Candidate targets were also highly abundant in the acanthocephalan body wall, through which these gutless parasites take up nutrients. Thus, the candidate targets are likely to be accessible to compounds that are orally administered to fish. Virtual ligand screening led to ten compounds, of which five appeared to be especially promising according to ADMET, GHS, and RO5 criteria: tadalafil, pranazepide, piketoprofen, heliomycin, and the nematicide derquantel.
The combination of genomics, transcriptomics, and proteomics led to a broadly applicable procedure for the cost- and time-saving identification of candidate target proteins in parasites. The ligands predicted to bind can now be further evaluated for their suitability in the control of acanthocephalans. The workflow has been deposited at the Galaxy workflow server under the URL tinyurl.com/yx72rda7 .
随着动物生产的扩大，寄生蠕虫的经济重要性日益增加。然而，由于特异性低，几种已建立的驱虫剂的应用会对受治疗的宿主和环境造成危害。此外，具有抗药性的寄生虫株数量不断增加，而几乎没有新的驱虫药被开发出来。在这里，我们提出了一种生物信息学工作流程，旨在减少开发针对寄生虫的新策略的时间和成本。该工作流程包括定量转录组学和蛋白质组学、3D 结构建模、结合位点预测和虚拟配体筛选。它用于棘头虫（刺头虫），棘头虫是鱼类养殖中的一种新出现的害虫。我们包括了来自四个鱼类物种（普通鲤鱼、欧洲鳗、薄唇鲻、塔巴圭）的三种棘头虫（Pomp horhynchus laevis、Neoechinorhynchus agilis、Neoechinorhynchus buttnerae）。
该工作流程导致棘头虫中有 11 个高度特异性的候选靶标。候选靶标在终末宿主和偶然宿主中表现出恒定和升高的转录丰度，提示其组成型表达和功能重要性。因此，相应蛋白质的损伤应该能够使棘头虫特异性和有效杀灭。候选靶标在棘头虫体壁中也高度丰富，这些无肠寄生虫通过体壁吸收营养。因此，候选靶标可能容易受到口服给予鱼类的化合物的影响。虚拟配体筛选得到了 10 种化合物，根据 ADMET、GHS 和 RO5 标准，其中 5 种化合物似乎特别有希望：他达拉非、普兰扎肽、匹克洛芬、海利霉素和杀线虫剂地喹氯铵。
基因组学、转录组学和蛋白质组学的结合为在寄生虫中节省成本和时间的候选靶标蛋白的识别提供了一种广泛适用的程序。预测结合的配体现在可以进一步评估它们在棘头虫控制中的适用性。该工作流程已在 Galaxy 工作流程服务器上提交，网址为 tinyurl.com/yx72rda7。
