Institute of Biological, Environmental and Rural Sciences (IBERS), Aberystwyth University, United Kingdom.
Department of Chemistry, Technical University of Munich, Germany.
PLoS Negl Trop Dis. 2021 Feb 18;15(2):e0008770. doi: 10.1371/journal.pntd.0008770. eCollection 2021 Feb.
Schistosomiasis is a neglected tropical disease that currently affects over 250 million individuals worldwide. In the absence of an immunoprophylactic vaccine and the recognition that mono-chemotherapeutic control of schistosomiasis by praziquantel has limitations, new strategies for managing disease burden are urgently needed. A better understanding of schistosome biology could identify previously undocumented areas suitable for the development of novel interventions. Here, for the first time, we detail the presence of G-quadruplexes (G4) and putative quadruplex forming sequences (PQS) within the Schistosoma mansoni genome. We find that G4 are present in both intragenic and intergenic regions of the seven autosomes as well as the sex-defining allosome pair. Amongst intragenic regions, G4 are particularly enriched in 3´ UTR regions. Gene Ontology (GO) term analysis evidenced significant G4 enrichment in the wnt signalling pathway (p<0.05) and PQS oligonucleotides synthetically derived from wnt-related genes resolve into parallel and anti-parallel G4 motifs as elucidated by circular dichroism (CD) spectroscopy. Finally, utilising a single chain anti-G4 antibody called BG4, we confirm the in situ presence of G4 within both adult female and male worm nuclei. These results collectively suggest that G4-targeted compounds could be tested as novel anthelmintic agents and highlights the possibility that G4-stabilizing molecules could be progressed as candidates for the treatment of schistosomiasis.
血吸虫病是一种被忽视的热带病，目前影响着全球超过 2.5 亿人。由于缺乏免疫预防疫苗，而且吡喹酮单一化学疗法控制血吸虫病的效果有限，因此迫切需要新的策略来控制疾病负担。更好地了解血吸虫生物学可以发现以前未被记录的适合开发新干预措施的领域。在这里，我们首次详细描述了曼氏血吸虫基因组中 G-四链体 (G4) 和假定的四链体形成序列 (PQS) 的存在。我们发现 G4 存在于七个常染色体和性别决定的全染色体对的基因内和基因间区域。在基因内区域，G4 在 3'UTR 区域特别丰富。基因本体论 (GO) 术语分析表明，Wnt 信号通路中存在显著的 G4 富集 (p<0.05)，并且从与 Wnt 相关的基因中合成的 PQS 寡核苷酸解析为平行和反平行的 G4 基序，这一点通过圆二色性 (CD) 光谱学得到了阐明。最后，我们利用一种称为 BG4 的单链抗 G4 抗体，证实了 G4 存在于成年雌性和雄性蠕虫核内。这些结果共同表明，G4 靶向化合物可以作为新型驱虫剂进行测试，并强调了 G4 稳定分子可能作为治疗血吸虫病的候选药物的可能性。
