title: Plasmodium falciparum parasites are killed by a transition state analogue of purine nucleoside phosphorylase in a primate animal model.
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.
authors.affiliation: Department of Biochemistry, Albert Einstein College of Medicine, Yeshiva University, Bronx, New York, United State of America.
authors.forename: María B
authors.initials: MB
authors.lastname: Cassera
authors.forename: Keith Z
authors.initials: KZ
authors.lastname: Hazleton
authors.forename: Emilio F
authors.initials: EF
authors.lastname: Merino
authors.forename: Nicanor
authors.initials: N
authors.lastname: Obaldia
authors.forename: Meng-Chiao
authors.initials: MC
authors.lastname: Ho
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Murkin
authors.forename: Richard
authors.initials: R
authors.lastname: DePinto
authors.forename: Jemy A
authors.initials: JA
authors.lastname: Gutierrez
authors.forename: Steven C
authors.initials: SC
authors.lastname: Almo
authors.forename: Gary B
authors.initials: GB
authors.lastname: Evans
authors.forename: Yarlagadda S
authors.initials: YS
authors.lastname: Babu
authors.forename: Vern L
authors.initials: VL
authors.lastname: Schramm
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000627:therapeutic use*; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy; D008954:Models, Biological; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000472:pathogenicity; D011073:Polyamines / Q000378:metabolism; D011323:Primates; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry*; D011687:Purines / Q000378:metabolism; D011759:Pyrrolidines / Q000627:therapeutic use*
chemical_list: C528507:4'-deaza-1'-aza-2'-deoxy-1'-(9-methylene)immucillin G; D000962:Antimalarials; D011073:Polyamines; D011687:Purines; D011759:Pyrrolidines; D011683:Purine-Nucleoside Phosphorylase; D000241:Adenosine; C030985:purine
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