Plasmodium spp. are the causative agents of malaria, killing nearly 600,000 people each year. Resistance of Plasmodium to chloroquine and artemisinin-based therapies accentuates the need for new drugs that target novel aspects of the parasite’s biology. Nearly all parasites in the phylum Apicocomplexa have an unusual organelle called the apicoplast, acquired through a secondary endosymbiotic event with algae. It participates in the biosynthesis of fatty acids, heme, iron-sulfur clusters, and isoprenoids and any defect in apicoplast metabolism or failure of the apicoplast to replicate and divide leads to the death of the organism. Additionally, lack of a human counterpart to the apicoplast makes apicoplast promising drug target. The 35-kb genome of apicoplast is replicated by select DNA replication enzymes of which the apicoplast DNA polymerase (apPOL) is unique to the parasite. The apPOLs from P. falciparum and P. vivax have 84% homology, while the most similar human DNA polymerases are the lesion bypass polymerases theta and nu (23 and 22% identity, respectively). This suggests that drugs targeted against the Pf-apPOL would also be effective in treating P. vivax infections with low human toxicity. Towards identifying inhibitors of apPOL, a high throughput screen of 400 compounds from the Open Malaria Box provided by MMV identified an inhibitor of apPOL with an IC50 of 0.8 ± 0.3 µM. Preliminary studies indicate that MMV666123 is specific for apPOL, with no inhibition of human DNA Pol or E. coli DNA Pol I. Also, MMV666123 inhibits the polymerase activity of apPOL but not its exonuclease activity, suggesting binding to the C-terminal polymerase domain of apPOL. Additionally, being from the malaria box substantiates anti-malarial activity of MMV666123. Presented here are initial design, synthesis and in-vitro evaluation efforts toward understanding the structural requirements of MMV666123 for inhibition of apPOL and identifying more potent and drug-like apPOL inhibitors.

Design, synthesis and evaluation of novel antimalarials targeting apicoplast DNA polymerase (apPOL) from P. falciparum

256th National Meeting (2018)

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