title: A class of potent antimalarials and their specific accumulation in infected erythrocytes.
abstract: During asexual development within erythrocytes, malaria parasites synthesize considerable amounts of membrane. This activity provides an attractive target for chemotherapy because it is absent from mature erythrocytes. We found that compounds that inhibit phosphatidylcholine biosynthesis de novo from choline were potent antimalarial drugs. The lead compound, G25, potently inhibited in vitro growth of the human malaria parasites Plasmodium falciparum and P. vivax and was 1000-fold less toxic to mammalian cell lines. A radioactive derivative specifically accumulated in infected erythrocytes to levels several hundredfold higher than in the surrounding medium, and very low dose G25 therapy completely cured monkeys infected with P. falciparum and P. cynomolgi.
authors.affiliation: CNRS UMR 5539, CP 107, CNRS UMR 5810, CP 22, Université Montpellier II, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
authors.forename: Kai
authors.initials: K
authors.lastname: Wengelnik
authors.forename: Valerie
authors.initials: V
authors.lastname: Vidal
authors.forename: Marie L
authors.initials: ML
authors.lastname: Ancelin
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Cathiard
authors.forename: Jean Louis
authors.initials: JL
authors.lastname: Morgat
authors.forename: Clemens H
authors.initials: CH
authors.lastname: Kocken
authors.forename: Michèle
authors.initials: M
authors.lastname: Calas
authors.forename: Socrates
authors.initials: S
authors.lastname: Herrera
authors.forename: Alan W
authors.initials: AW
authors.lastname: Thomas
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Vial
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D001029:Aotus trivirgatus; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004912:Erythrocytes / Q000378:metabolism / Q000469:parasitology*; D006801:Humans; D008253:Macaca mulatta; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D016780:Malaria, Vivax / Q000188:drug therapy / Q000469:parasitology; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins / Q000037:antagonists & inhibitors; D018512:Parasitemia / Q000188:drug therapy; D010713:Phosphatidylcholines / Q000096:biosynthesis; D010961:Plasmodium / Q000187:drug effects*; D016789:Plasmodium cynomolgi / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D010966:Plasmodium vivax / Q000187:drug effects; D011759:Pyrrolidines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: C448986:1,16-hexadecamethylenebis(N-methylpyrrolidinyl); D000962:Antimalarials; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D010713:Phosphatidylcholines; D011759:Pyrrolidines; C065637:choline transporter