Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model

María B. Cassera, Keith Z. Hazleton, Emilio F. Merino, Nicanor Obaldia, Meng Chiao Ho, Andrew S. Murkin, Richard DePinto, Jemy A. Gutierrez, Steven C. Almo, Gary B. Evans, Yarlagadda S. Babu, Vern L. Schramm

Research output: Contribution to journalArticle

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Abstract

Plasmodium 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.

Original languageEnglish (US)
Article numbere26916
JournalPLoS One
Volume6
Issue number11
DOIs
StatePublished - Nov 11 2011

Fingerprint

Purine-Nucleoside Phosphorylase
phosphorylase
nucleosides
Plasmodium falciparum
purines
Primates
Parasites
Animals
Animal Models
animal models
parasites
Plasmodium
Aotus (Cebidae)
Malaria
Salvaging
Chemical stability
Antimalarials
Polyamines
Metabolites
Toxicity

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model. / Cassera, María B.; Hazleton, Keith Z.; Merino, Emilio F.; Obaldia, Nicanor; Ho, Meng Chiao; Murkin, Andrew S.; DePinto, Richard; Gutierrez, Jemy A.; Almo, Steven C.; Evans, Gary B.; Babu, Yarlagadda S.; Schramm, Vern L.

In: PLoS One, Vol. 6, No. 11, e26916, 11.11.2011.

Research output: Contribution to journalArticle

Cassera, MB, Hazleton, KZ, Merino, EF, Obaldia, N, Ho, MC, Murkin, AS, DePinto, R, Gutierrez, JA, Almo, SC, Evans, GB, Babu, YS & Schramm, VL 2011, 'Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model', PLoS One, vol. 6, no. 11, e26916. https://doi.org/10.1371/journal.pone.0026916
Cassera, María B. ; Hazleton, Keith Z. ; Merino, Emilio F. ; Obaldia, Nicanor ; Ho, Meng Chiao ; Murkin, Andrew S. ; DePinto, Richard ; Gutierrez, Jemy A. ; Almo, Steven C. ; Evans, Gary B. ; Babu, Yarlagadda S. ; Schramm, Vern L. / Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model. In: PLoS One. 2011 ; Vol. 6, No. 11.
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