Inhibition of Plasmodium falciparum proliferation in vitro by antisense oligodeoxynucleotides against malarial topoisomerase II.
The development of new effective antimalarial agents is urgently needed due to the ineffectiveness of current drug regimes on the most virulent human malaria parasite Plasmodium falciparum. Antisense (AS) oligodeoxynucleotides (ODNs) have shown promise as chemotherapeutic agents. Phosphorothioate AS ODNs against different regions of P. falciparum topoisomerase II gene were investigated. Chloroquine- and pyrimethamine-resistant P. falciparum K1 strain was exposed to phosphorothioate AS ODNs for 48 h and growth was determined by flow cytometric assay or by microscopic assay. Exogenous delivery of phosphorothioate AS ODNs between 0.01 and 0.5 microM significantly inhibited parasite growth compared with sense sequence controls suggesting sequence specific inhibition. This inhibition was shown to occur during maturation stages, with optimal inhibition being detected after 36 h. These results should prove useful in future designs of novel antimalarial agents.
Noonpakdee
Wilai
W
Department of Biochemistry, Faculty of Science, Mahidol University, Bangkok 10400, Thailand. scwnp@mahidol.ac.th
Pothikasikorn
Jinrapa
J
Nimitsantiwong
Wirat
W
Wilairat
Prapon
P
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology* / Q000627:therapeutic use; D004250:DNA Topoisomerases, Type II / Q000235:genetics* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D013873:Thionucleotides / Q000378:metabolism / Q000494:pharmacology*
D000962:Antimalarials; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D004250:DNA Topoisomerases, Type II