Characterization of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial chugs

Biagini, Giancarlo ORCID: https://orcid.org/0000-0001-6356-6595, Pasini, E. M., Hughes, Ruth, De Koning, H. P., Vial, H. J., O'Neill, P. M., Ward, Stephen ORCID: https://orcid.org/0000-0003-2331-3192 and Bray, Patrick (2004) 'Characterization of the choline carrier of Plasmodium falciparum: a route for the selective delivery of novel antimalarial chugs'. Blood, Vol 104, Issue 10, pp. 3372-3377.

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Abstract

New drugs are urgently needed to combat the growing problem of drug resistance in Plasmodium falciparum malaria. The infected erythrocyte is a multicompartmental system, and its transporters are of interest as drug targets in their own right and as potential routes for the delivery of antimalarial drugs. Choline is an important nutrient that penetrates infected erythrocyte membranes through the endogenous carrier and through parasite-induced permeability pathways, but nothing is known about its transport into the intracellular parasite. Here we present the first characterization of choline transport across the parasite membrane. Transport exhibits Michaelis-Menten kinetics with an apparent K-m of 25.0 +/- 3.5 muM for choline. The carrier is inhibitor-sensitive, temperature-dependent, and Na+-independent, and it is driven by the proton-motive force. Highly active bis-amidine and bis-quaternary ammonium compounds are also known to penetrate the host erythrocyte membrane through parasite-induced permeability pathways. Here, we demonstrate that the parasite choline transporter mediates the delivery of these compounds to the intracellular parasite. Thus, the induced permeability pathways in the host erythrocyte membrane and the parasite choline transporter described here form a cooperative transport system that shows great promise for the selective targeting of new agents for the chemotherapy of malaria. (C) 2004 by The American Society of Hematology.

Item Type:	Article
Uncontrolled Keywords:	intraerythrocytic malaria parasite infected erythrocytes phosphatidylcholine biosynthesis phospholipid-metabolism transport analogs chemotherapy inhibition growth target
Subjects:	QV Pharmacology > Anti-Inflammatory Agents. Anti-Infective Agents. Antineoplastic Agents > QV 256 Antimalarials QX Parasitology > Protozoa > QX 135 Plasmodia WC Communicable Diseases > Tropical and Parasitic Diseases > WC 750 Malaria WH Hemic and Lymphatic Systems > Hematologic Diseases. Immunologic Factors. Blood Banks > WH 150 Erythrocytes
Faculty: Department:	Groups (2002 - 2012) > Molecular & Biochemical Parasitology Group
Digital Object Identifer (DOI):	https://doi.org/10.1182/blood-2004-03-1084
Depositing User:	Sarah Lewis-Newton
Date Deposited:	25 Jan 2012 16:25
Last Modified:	17 Jul 2020 10:59
URI:	https://archive.lstmed.ac.uk/id/eprint/2128

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