Antimalarial antisense activity of hexitol nucleic acids.
Antisense oligonucleotides and ribozymes have shown promise both as antimalarial agents and as tools for identifying genes vital for parasite survival. This task is urgent due to the ineffectiveness of current drug regimes on the most virulent human malarial parasite, Plasmodium falciparum. The development of new ways to modify and/or protect conventional phosphodiester oligonucleotides to improve nuclease resistance is also important. We assessed the effect of antisense oligonucleotides containing phosphorylated anhydrohexitols in suppressing the growth of P. falciparum in culture. The modified oligonucleotides were able to inhibit parasite growth in a sequence-specific manner, but not as well as the phosphorothioated antisense oligonucleotides, which are effective antimalarials at submicromolar concentrations. Two reasons are suggested: the absence of RNase H activation and differences in membrane transport.
Flores
M V
MV
School of Biochemistry and Molecular Genetics, The University of New South Wales, Sydney, Australia. m.flores@unsw.edu.au
Atkins
D
D
Stewart
T S
TS
van Aerschot
A
A
Herdewijn
P
P
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D001483:Base Sequence; D006598:Hexosediphosphates; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development
D000962:Antimalarials; D006598:Hexosediphosphates; D016376:Oligonucleotides, Antisense