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Malaria merozoite surface protein antisense oligodeoxynucleotides lack antisense activity but function as polyanions
R Kanagaratnam1, K Misiura, G Rebowski
1Division of Life Sciences, Institute of Fundamental Studies, Kandy, Sri Lanka.
Abstract:
The effects on malaria parasite growth of antisense and sense oligodeoxynucleoside phosphorothioates based on a merozoite surface protein mRNA was examined. Specific antisense effects of the oligonucleotides could not be demonstrated over three cycles of schizogony or when added as a complex with cationic liposomes. Antisense and sense oligonucleotides however, inhibit merozoite invasion of red blood cells at similar concentrations to dextran sulphate, a polyanion, as determined by microscopy and [3H]hypoxanthine incorporation into DNA. Neutralisation of the negative charge on the oligonucleotides by binding to cationic lipid liposomes, prevented the inhibition of merozoite invasion. We postulate that oligonucleotides because of their polyanionic nature interfere with the binding of merozoites to receptors on red blood cells and that polyanions may be useful in malaria therapy.
Insights
Antisense and sense oligonucleotides, charged molecules, were found to inhibit malaria parasite invasion of red blood cells. This suggests polyanions could be a novel therapeutic approach for malaria.
Area of Science:
- Parasitology
- Molecular Biology
- Drug Discovery
Background:
- Malaria remains a significant global health challenge, necessitating novel therapeutic strategies.
- Merozoite surface proteins are crucial for malaria parasite invasion of red blood cells.
Purpose of the Study:
- To investigate the effects of antisense and sense oligodeoxynucleoside phosphorothioates on malaria parasite growth and red blood cell invasion.
- To explore the potential of polyanionic compounds as antimalarial agents.
Main Methods:
- Oligodeoxynucleoside phosphorothioates targeting merozoite surface protein mRNA were synthesized.
- Inhibition of merozoite invasion was assessed using microscopy and [3H]hypoxanthine incorporation.
- The role of oligonucleotide charge was investigated using cationic liposomes.
Main Results:
- Specific antisense effects were not demonstrated during parasite schizogony.
- Both antisense and sense oligonucleotides inhibited merozoite invasion of red blood cells.
- Neutralizing the negative charge of oligonucleotides with cationic liposomes abolished the inhibitory effect.
Conclusions:
- Oligonucleotides, due to their polyanionic nature, interfere with merozoite binding to red blood cells.
- Polyanions show promise as a potential therapeutic strategy for malaria treatment.