K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum\nmalaria that threatens the long-term clinical utility of artemisinin-based combination\ntherapies, the cornerstone of modern day malaria treatment. Here we describe a\nmultinational drug discovery programme that has delivered a synthetic tetraoxane-based\nmolecule, E209, which meets key requirements of the Medicines for Malaria Venture drug\ncandidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of\nP. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models,\nproduces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic\nand pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies\nwith transgenic parasites expressing variant forms of K13 show no cross-resistance with the\nC580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next\ngeneration endoperoxide with combined pharmacokinetic and pharmacodynamic features\nthat overcome the liabilities of artemisinin derivatives.
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