De Cian Anne, Grellier Philippe, Mouray Elisabeth, Depoix Delphine, Bertrand Hélène, Monchaud David, Teulade-Fichou Marie-Paule, Mergny Jean-Louis, Alberti Patrizia
INSERM, U565, Paris Cedex 05, 75231, France.
Chembiochem. 2008 Nov 3;9(16):2730-9. doi: 10.1002/cbic.200800330.
The increasing resistance of Plasmodium falciparum to the most commonly used antimalarial drugs makes it necessary to identify new therapeutic targets. The telomeres of the parasite could constitute an attractive target. They are composed of repetitions of a degenerate motif ((5')GGGTTYA(3'), where Y is T or C), different from the human one ((5')GGGTTA(3')). In this report we investigate the possibility of targeting Plasmodium telomeres with G-quadruplex ligands. Through solution hybridisation assays we provide evidence of the existence of a telomeric 3' G-overhang in P. falciparum genomic DNA. Through UV spectroscopy studies we demonstrate that stable G-quadruplex structures are formed at physiological temperature by sequences composed of the degenerate Plasmodium telomeric motif. Through a FRET melting assay we show stabilisation of Plasmodium telomeric G-quadruplexes by a variety of ligands. Many of the tested ligands display strong quadruplex versus duplex selectivity, but show little discrimination between human and Plasmodium telomeric quadruplexes.
恶性疟原虫对最常用抗疟药物的耐药性不断增加，因此有必要确定新的治疗靶点。疟原虫的端粒可能是一个有吸引力的靶点。它们由一个简并基序（(5')GGGTTYA(3')，其中Y为T或C）的重复序列组成，与人类的端粒基序（(5')GGGTTA(3')）不同。在本报告中，我们研究了用G-四链体配体靶向疟原虫端粒的可能性。通过溶液杂交试验，我们提供了恶性疟原虫基因组DNA中端粒3' G-突出端存在的证据。通过紫外光谱研究，我们证明了由简并疟原虫端粒基序组成的序列在生理温度下形成了稳定的G-四链体结构。通过荧光共振能量转移熔解试验，我们展示了多种配体对疟原虫端粒G-四链体的稳定作用。许多测试的配体对四链体与双链体具有很强的选择性，但对人类和疟原虫端粒四链体的区分能力较弱。
