Antisense oligonucleotides targeting malarial aldolase inhibit the asexualerythrocytic stages of Plasmodium falciparum

A major obstacle in the global effort to control malaria is the paucity of anti-malarial drugs. This is compounded by the continuing emergence and spr ead of resistance to old and new anti-malarial drugs in the malarial parasi tes. Here we describe the anti-malarial effect of phosphorothioate antisens e (AS) oligodeoxynucleotides (ODNs) targeting the aldolase enzyme of Plasmo dium falciparum, using the asexual blood stages of the parasite grown in vi tro. The blood stages of P. falciparum depend almost entirely on the energy produced by their own glycolysis. Aldolase, the fourth enzyme of the glyco lytic pathway, is highly upregulated during the malarial 48-h life cycle. W e found that the mRNA of this enzyme can be inhibited, in a sequence specif ic manner, using AS-ODN to the splice sites on the pre-mRNA of malarial ald olase. At the enzyme level, both specific AS-ODNs for the splice sites, as well as for the translation inititation site on mature mRNA, can inhibit al dolase enzyme activity within the trophozoites of P. falciparum. Furthermor e, this downregulation of the malarial aldolase results in a reduction in t he production of ATP within the parasite. Finally, the treatment reduces pa rasitemia. In summary, AS-ODNs targeting the aldolase gene of P. falciparum can interfere with the blood-stage life cycle of this parasite in vitro by inhibiting the expression of the enzyme aldolase which results in decrease d malarial glycolysis and energy production. Thus, we conclude that blockad e of the expression of malarial glycolytic enzymes using specific AS-ODNs h as the potential of a new anti-malarial strategy. (C) 1999 Elsevier Science B.V. All rights reserved.