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Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of <jats:italic>P. falciparum<\/jats:italic> and <jats:italic>P. vivax in vitro<\/jats:italic>, is efficacious against <jats:italic>P. falciparum<\/jats:italic> in <jats:italic>in vivo<\/jats:italic> rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. <jats:italic>In vitro<\/jats:italic> studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives.<\/jats:p>","DOI":"10.1038\/ncomms15159","type":"journal-article","created":{"date-parts":[[2017,5,24]],"date-time":"2017-05-24T11:39:41Z","timestamp":1495625981000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":58,"title":["A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance"],"prefix":"10.1038","volume":"8","author":[{"given":"Paul M.","family":"O\u2019Neill","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard K.","family":"Amewu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan A.","family":"Charman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sunil","family":"Sabbani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina F.","family":"Gn\u00e4dig","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judith","family":"Straimer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6753-8938","authenticated-orcid":false,"given":"David A.","family":"Fidock","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma R.","family":"Shore","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalie L.","family":"Roberts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael H.-L.","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"W. 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