Pharmacogenomic analyses of targeting the AT-rich malaria parasite genome with AT-specific alkylating drugs.
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 approximately 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.


CONCLUSIONS
Super-AT islands, identified as unique domains in the P. falciparum genome with presumably crucial functions, offer therapeutically exploitable opportunity for new antimalarial strategies.
Woynarowski
Jan M
JM
Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA. woynarowskij@mail.nih.gov
Krugliak
Miriam
M
Ginsburg
Hagai
H
D000477:Alkylating Agents / Q000494:pharmacology*; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology*; D001482:Base Composition; D001572:Benzofurans; D001665:Binding Sites; D002503:Centromere; D003509:Cyclohexanecarboxylic Acids / Q000737:chemistry / Q000494:pharmacology; D053138:Cyclohexenes / Q000737:chemistry / Q000494:pharmacology; D016054:DNA, Protozoan / Q000378:metabolism; D000080890:Duocarmycins; D044404:Genomic Islands / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010597:Pharmacogenetics; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics; D012680:Sensitivity and Specificity; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000477:Alkylating Agents; D000962:Antimalarials; D001572:Benzofurans; D003509:Cyclohexanecarboxylic Acids; D053138:Cyclohexenes; D016054:DNA, Protozoan; D000080890:Duocarmycins; D007211:Indoles; C060090:adozelesin; D014508:Urea; C072257:bizelesin