Abstracts Category : Other

In vitroefficacy assessment of targeted antimalarial drugs synthesizedfollowing in silico design

by Dikeledi MA Matlebjane

Malaria is a major public health problem that affectsmillions of lives globally. The increased burden of malariarequires new interventions that will address the eradication of thedisease. Current interventions include vector control by usinginsecticide-treated bed nets and indoor residual spraying, andantimalarial drugs to control the parasite. Parasite resistancehas been reported for the currently used effective antimalarialdrugs. To pre-empt the impact of parasite resistance a continueddevelopment of new antimalarial drugs that have novel mechanismsof action should be pursued. Antimalarial drug discovery requiresthat potential antimalarial drugs should have different drugtargets to those already targeted, to lower the chances ofresistance. Potential antimalarial drugs should preferably providea single radical cure to prevent reproduction at all life cyclestages. This study tested the effects of in silico designedcompounds targeting plasmodial Ca2+- dependent protein kinases(CDPK) 1 & 4, FIKK kinases and bromodomain proteins on thePlasmodium parasite. These enzymes are involved in gene regulationand are important factors during gene transcription. In P.falciparum the gatekeeper kinases contain small hydrophobicpockets near the ATP-binding site. These hydrophobic pockets allowfor selective inhibition of these proteins at the ATP-bindingsite. The compounds were tested in vitro to determine theirantiplasmodial activity. These compounds are shown to be potentialinhibitors of the intra-erythrocytic P. falciparum parasites asthree of the compounds showed selective cytotoxic activity at lessthan 1 M against the chloroquine sensitive laboratory strains(3D7 and NF54). Even though the proteins targeted by thesecompounds have been previously indicated to play a role atspecific stages during the parasites life cycle, the compoundstested here were not able to target the sexual gametocyte stages ofthe Plasmodium parasite. Further optimisation of these compoundsshould be performed to improve activity against both the asexualand sexual stages of the parasites.Advisors/Committee Members: Cromarty, Allan Duncan (advisor), Birkholtz, Lyn-Marie (coadvisor).