Plasmodium telomeric sequences: structure, stability and quadruplex targeting by small compounds

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.