Basic biochemical investigations as rationale for the design of original antimalarial drugs. An example of phospholipid metabolism.
The future of antimalarial chemotherapy is particularly alarming in view of the spread of parasite cross-resistances to drugs that are not even structurally related. Only the availability of new pharmacological models will make it possible to select molecules with novel mechanisms of action, thus delaying resistance and allowing the development of new chemotherapeutic strategies. We reached this objective in mice. Our approach is hunged on fundamental and applied research begun in 1980 to investigate the phospholipid (PL) metabolism of intraerythrocytic Plasmodium. This metabolism is abundant, specific and indispensable for the production of Plasmodium membranes. Any drug able to interfere with this Plasmodium membranes. Any drug able to interfere with this metabolism blocks parasitic development. The most effective interference yet found involves blockage of the choline transporter, which supplies Plasmodium with choline for the synthesis of phosphatidylcholine, its major PL, this is a limiting step in the pathway. The drug sensitivity threshold is much lower for the parasite, which is more dependent on this metabolism than host cells. The compounds show in vitro activity against P. falciparum at 1 to 10 nM. They show a very low toxicity against a lymphoblastoid cell line, demonstrating a total absence of correlation between growth inhibition of parasites and lymphoblastoid cells. They show antimalarial activity in vivo, in the P. berghei or P. chabaudi/mouse system, at doses 20- to 100-fold lower than their acute toxicity limit. The bioavailability of a radiolabeled form of the product seemed to be advantageous (slow blood clearance and no significant concentration in tissues). Lastly, the compounds are inexpensive to produce. They are stable and water-soluble.
Laboratoire de Chimie Organique Structurale, CNRS URA 530, Montpilleir, France.
H J
HJ
Vial
M L
ML
Angelin
N
N
Elabbadi
M
M
Calas
G
G
Cordinas
L
L
Giral
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004910:Erythrocyte Membrane / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008288:Malaria / Q000097:blood / Q000188:drug therapy / Q000469:parasitology; D008563:Membrane Lipids / Q000378:metabolism*; D026901:Membrane Transport Proteins; D051379:Mice; D010743:Phospholipids / Q000378:metabolism*; D010961:Plasmodium / Q000187:drug effects* / Q000378:metabolism
D000962:Antimalarials; D002352:Carrier Proteins; D008563:Membrane Lipids; D026901:Membrane Transport Proteins; D010743:Phospholipids; C065637:choline transporter; D002784:Cholesterol; D002794:Choline