Authors

M Rajab¹;  ¹ University of Salford

Discussion

Calcium, calcium channels along with calmodulin (CaM) play important roles in human RBCs and within Plasmodium falciparum parasites. Studies have shown that calcium levels are higher in infected RBCs than non-infected ones and interfering with calcium signalling can lead to degeneration and eventually parasite death. Likewise several antimalarial drugs are reported to have anti-CaM activity. This supports results of a repositioning study carried out at the University of Salford were 700 patent expired drugs were screened against the multidrug resistant K1 P. falciparum strain. The results showed several calcium channel blockers and CaM inhibitors to have antimalarial activity. The work presented here covers the synthesis and investigation of the antimalarial efficacy of a calcium channel blocker and CaM inhibitor MR15 and numerous of its synthetic analogues. The initial results from the in vitro phenotypic screens on the multidrug resistant K1 P. falciparum strain, HepG2 cytotoxicity assay, hERG safety test, and stage specificity analysis were promising and thus supported further studies. Other work presented here includes CalcuSyn based combination studies of MR15 with current anti-malarial drugs and other calcium channel blockers. Additionally ongoing optimisation using fluorescent dyes is being carried out to detect fluctuations of calcium levels within P. falciparum infected RBCs using flow cytometry.