title: Transport and pharmacodynamics of albitiazolium, an antimalarial drug candidate.
abstract: OBJECTIVE
  Choline analogues, a new type of antimalarials, exert potent in vitro and in vivo antimalarial activity. This has given rise to albitiazolium, which is currently in phase II clinical trials to cure severe malaria. Here we dissected its mechanism of action step by step from choline entry into the infected erythrocyte to its effect on phosphatidylcholine (PC) biosynthesis.
  
  
  METHODS
  We biochemically unravelled the transport and enzymatic steps that mediate de novo synthesis of PC and elucidated how albitiazolium enters the intracellular parasites and affects the PC biosynthesis.
  
  
  RESULTS
  Choline entry into Plasmodium falciparum-infected erythrocytes is achieved both by the remnant erythrocyte choline carrier and by parasite-induced new permeability pathways (NPP), while parasite entry involves a poly-specific cation transporter. Albitiazolium specifically prevented choline incorporation into its end-product PC, and its antimalarial activity was strongly antagonized by choline. Albitiazolium entered the infected erythrocyte mainly via a furosemide-sensitive NPP and was transported into the parasite by a poly-specific cation carrier. Albitiazolium competitively inhibited choline entry via the parasite-derived cation transporter and also, at a much higher concentration, affected each of the three enzymes conducting de novo synthesis of PC.
  
  
  CONCLUSIONS
  Inhibition of choline entry into the parasite appears to be the primary mechanism by which albitiazolium exerts its potent antimalarial effect. However, the pharmacological response to albitiazolium involves molecular interactions with different steps of the de novo PC biosynthesis pathway, which would help to delay the development of resistance to this drug.
authors.affiliation: Dynamique des Interactions Membranaires Normales et Pathologiques, CNRS UMR 5235, Université Montpellier II, Montpellier, France.
authors.forename: S
authors.initials: S
authors.lastname: Wein
authors.forename: M
authors.initials: M
authors.lastname: Maynadier
authors.forename: Y
authors.initials: Y
authors.lastname: Bordat
authors.forename: J
authors.initials: J
authors.lastname: Perez
authors.forename: S
authors.initials: S
authors.lastname: Maheshwari
authors.forename: P
authors.initials: P
authors.lastname: Bette-Bobillo
authors.forename: C
authors.initials: C
authors.lastname: Tran Van Ba
authors.forename: D
authors.initials: D
authors.lastname: Penarete-Vargas
authors.forename: L
authors.initials: L
authors.lastname: Fraisse
authors.forename: R
authors.initials: R
authors.lastname: Cerdan
authors.forename: H
authors.initials: H
authors.lastname: Vial
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000378:metabolism*; D001692:Biological Transport / Q000502:physiology; D002794:Choline / Q000378:metabolism; D004912:Erythrocytes / Q000469:parasitology*; D006801:Humans; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000096:biosynthesis*; D010963:Plasmodium falciparum / Q000187:drug effects / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism*
chemical_list: C499114:1,12-bis(4-methyl-5-(2-hydroxyethyl)thiazol-3-ium-3-yl)dodecane; D000962:Antimalarials; D010713:Phosphatidylcholines; D013844:Thiazoles; D002794:Choline