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dc.contributor.authorCassera, Maria B.en_US
dc.contributor.authorHazleton, Keith Z.en_US
dc.contributor.authorMerino, Emilio F.en_US
dc.contributor.authorObaldia, Nicanor, IIIen_US
dc.contributor.authorHo, Meng-Chiaoen_US
dc.contributor.authorMurkin, Andrew S.en_US
dc.contributor.authorDePinto, Richarden_US
dc.contributor.authorGutierrez, Jemy A.en_US
dc.contributor.authorAlmo, Steven C.en_US
dc.contributor.authorEvans, Gary B.en_US
dc.contributor.authorBabu, Yarlagadda S.en_US
dc.contributor.authorSchramm, Vern L.en_US
dc.description.abstractPlasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent.en_US
dc.rightsCreative Commons Attribution 4.0 Internationalen_US
dc.titlePlasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Modelen_US
dc.typeArticle - Refereeden_US
dc.description.versionPeer Revieweden_US
dc.title.serialPLOS ONEen_US

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Creative Commons Attribution 4.0 International
License: Creative Commons Attribution 4.0 International