title: Pharmacogenomic analyses of targeting the AT-rich malaria parasite genome with AT-specific alkylating drugs.
abstract: 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.
authors.affiliation: Department of Radiation Oncology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, USA. woynarowskij@mail.nih.gov
authors.forename: Jan M
authors.initials: JM
authors.lastname: Woynarowski
authors.forename: Miriam
authors.initials: M
authors.lastname: Krugliak
authors.forename: Hagai
authors.initials: H
authors.lastname: Ginsburg
mesh_terms: 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
chemical_list: 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