TY - JOUR
T1 - Pharmacogenomic analyses of targeting the AT-rich malaria parasite genome with AT-specific alkylating drugs
AU - Woynarowski, Jan M.
AU - Krugliak, Miriam
AU - Ginsburg, Hagai
PY - 2007/7
Y1 - 2007/7
N2 - 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.
AB - 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.
KW - A/T-rich
KW - Adozelesin
KW - Antimalarial activity
KW - AT islands
KW - Bizelesin
KW - Centromeres
KW - Malaria
KW - Matrix attachment regions (MARs, S/MARs)
KW - Nucleosome-free regions
KW - Plasmodium falciparum
UR - http://www.scopus.com/inward/record.url?scp=34249938047&partnerID=8YFLogxK
U2 - 10.1016/j.molbiopara.2007.04.009
DO - 10.1016/j.molbiopara.2007.04.009
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C2 - 17524501
AN - SCOPUS:34249938047
SN - 0166-6851
VL - 154
SP - 70
EP - 81
JO - Molecular and Biochemical Parasitology
JF - Molecular and Biochemical Parasitology
IS - 1
ER -