Title : Novel antimalarial compound 2741-19 synergistically kills P. falciparum in vitro with artemisinin combination therapy partner drug, piperaquine
Abstract:
Plasmodium falciparum malaria infects 300-500 million individuals and accounts for over 600,00 deaths each year with the majority of deaths occurring in children under 5 years of age living in sub-Saharan Africa. In the past several years, morbidity and mortality due to P. falciparum have increased and the spread of parasites resistant to artemisinin, the mainstay of treatment, threatens to exacerbate this trend, underscoring the urgent need to identify novel antimalarial drugs. Previously, we identified a novel antimalarial small molecule drug, 2741-19, that binds with PfGARP, a malarial protein expressed on the exofacial surface of infected human erythrocytes. This drug kills malaria parasites with an IC50 of 50nM with no observable toxicity to mammalian cells. To forestall the development of resistance, P. falciparum infections are treated with artemisinin-based combination drug therapy. A key partner drug for artemisinin is the 4-aminoquinoline, piperaquine. To assess the potential for synergy in parasite killing between 2741-19 and piperaquine, we performed in vitro parasite growth assays using checkerboard dilution of these compounds. We quantified synergy using four mathematical models including, Loewe Additivity, Bliss Independence, Highest Single Agent (HSA), and Zero Interaction Potential (ZIP). In all models, 2741-19 demonstrated significant synergy with piperaquine in mediating parasite killing reflecting greater parasite killing than would be expected if the interaction were merely additive. This result suggests that 2741-19 has a mechanism of action that is distinct from piperaquine which kills parasites by inhibiting the detoxification of heme. These findings support further evaluation of 2741-19 in combination with artemisinin partner drugs as promising candidates for a next generation of antimalarial combination therapies.
