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Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model

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dc.contributor.authorCassera, Maria B.en
dc.contributor.authorHazleton, Keith Z.en
dc.contributor.authorMerino, Emilio F.en
dc.contributor.authorObaldia, Nicanor, IIIen
dc.contributor.authorHo, Meng-Chiaoen
dc.contributor.authorMurkin, Andrew S.en
dc.contributor.authorDePinto, Richarden
dc.contributor.authorGutierrez, Jemy A.en
dc.contributor.authorAlmo, Steven C.en
dc.contributor.authorEvans, Gary B.en
dc.contributor.authorBabu, Yarlagadda S.en
dc.contributor.authorSchramm, Vern L.en
dc.contributor.departmentBiochemistryen
dc.date.accessioned2018-11-05T15:13:16Zen
dc.date.available2018-11-05T15:13:16Zen
dc.date.issued2011-11-11en
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
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1371/journal.pone.0026916en
dc.identifier.eissn1932-6203en
dc.identifier.issue11en
dc.identifier.othere26916en
dc.identifier.pmid22096507en
dc.identifier.urihttp://hdl.handle.net/10919/85644en
dc.identifier.volume6en
dc.language.isoenen
dc.publisherPLOSen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titlePlasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Modelen
dc.title.serialPLOS ONEen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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