Pharmacogenomic analyses of targeting the AT-rich malaria parasite genome with AT-specific alkylating drugs
- 作者：Jan M. Woynarowski ; Miriam Krugliak ; Hagai Ginsburg
- 关键词：Plasmodium falciparum ; Malaria ; A/T-rich ; AT islands ; Matrix attachment regions (MARs ; S/MARs) ; Centromeres ; Nucleosome-free regions ; Antimalarial activity ; Adozelesin ; Bizelesin
- 刊名：Molecular and Biochemical Parasitology
- 出版年：2007
- 期刊代码：108_01666851
- 类别：bio
- 出版时间：July 2007
- 卷：154
- 期：1
- 页码：70-81
- 文件大小：1079 K
摘要
Human malaria parasites, including the most lethal Plasmodium falciparum, are increasingly resistant to existing antimalarial drugs. One remarkable opportunity to selectively target P. falciparum stems from the unique AT-richness of its genome (80%A/T, relative to 60%in human DNA). To rationally explore this opportunity, we used drugs (adozelesin and bizelesin) which distinctly target AT-rich minisatellites and an in silico approach for genome-wide analysis previously experimentally validated in human cells [Woynarowski JM, Trevino AV, Rodriguez KA, Hardies SC, Benham CJ. AT-rich islands in genomic DNA as a novel target for AT-specific DNA-reactive antitumor drugs. J Biol Chem 2001;276:40555–66]. Both drugs demonstrate a potent, rapid and irreversible inhibition of the cultured P. falciparum (50%inhibition at 110 and 10 ± 2.3 pM, respectively). This antiparasital activity reflects most likely drug binding to specific super-AT-rich regions. Relative to the human genome, the P. falciparum genome shows 3.9- and 7-fold higher frequency of binding sites for adozelesin and bizelesin, respectively. The distribution of these sites is non-random with the most prominent clusters found in large unique minisatellites [median size 3.5 kbp of nearly pure A/T, with multiple converging repeats but no shared consensus other than (A/T)n]. Each of the fourteen P. falciparum chromosomes contains only one such “super-AT island” located within 3–7.5 kbp of gene-free and nucleosome-free loci. Important functions of super-AT islands are suggested by their exceptional predicted potential to serve as matrix attachment regions (MARs) and a precise co-localization with the putative centromeres.
Conclusion
Super-AT islands, identified as unique domains in the P. falciparum genome with presumably crucial functions, offer therapeutically exploitable opportunity for new antimalarial strategies.