Non-sequence-specific antimalarial activity of oligodeoxynucleotides.
The effects of exogenously applied oligodeoxynucleotides on Plasmodium falciparum proliferation was investigated. A fluorescence-activated cell sorter assay was employed to measure parasitemia after administration of either phosphodiester or phosphorothioate oligodeoxynucleotides. We report sequence-independent antimalarial activity preferentially with phosphorothioate congeners with IC50 values in the 1-2 microM range. Phosphorothioate oligodeoxynucleotides which were antisense, sense or nonsense to Plasmodium mRNA, as well as homopolymers (30-mers containing all A or T bases) were equally effective inhibitors of parasitemia. The antimalarial activity was dependent upon oligomer length, concentration, and time of addition to the cultures but was independent of the parasite strain tested. Four P. falciparum strains, including a multi-drug-resistant strain (MDR-K), a drug-sensitive strain (FCR-3), a erythrocyte membrane sialic acid-independent strain (7G8) and a strain isolated from a cerebral malaria patient (CM-87) were equally susceptible to treatment with a phosphorothioate oligomer. Inhibition of red cell invasion is primarily responsible for the observed decrease in proliferation as determined by a study of parasite maturation in the presence of a 30-mer nonsense phosphorothioate oligodeoxynucleotide.
Clark
D L
DL
Department of Biochemistry and Molecular Biology, Georgetown University, Washington, DC 20007.
Chrisey
L A
LA
Campbell
J R
JR
Davidson
E A
EA
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology*; D001483:Base Sequence; D016054:DNA, Protozoan / Q000235:genetics; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D066298:In Vitro Techniques; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000235:genetics / Q000494:pharmacology*; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D013329:Structure-Activity Relationship
D000962:Antimalarials; D016054:DNA, Protozoan; D009838:Oligodeoxyribonucleotides; D016376:Oligonucleotides, Antisense