A class of potent antimalarials and their specific accumulation in infected erythrocytes.
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.
Wengelnik
Kai
K
CNRS UMR 5539, CP 107, CNRS UMR 5810, CP 22, Université Montpellier II, Place E. Bataillon, 34095 Montpellier Cedex 5, France.
Vidal
Valerie
V
Ancelin
Marie L
ML
Cathiard
Anne-Marie
AM
Morgat
Jean Louis
JL
Kocken
Clemens H
CH
Calas
Michèle
M
Herrera
Socrates
S
Thomas
Alan W
AW
Vial
Henri J
HJ
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
C448986:1,16-hexadecamethylenebis(N-methylpyrrolidinyl); D000962:Antimalarials; D049990:Membrane Transport Modulators; D026901:Membrane Transport Proteins; D010713:Phosphatidylcholines; D011759:Pyrrolidines; C065637:choline transporter