Combinatorial Chemistry & High Throughput Screening, 2005, 8, 81-88 81 The New Permeability Pathways: Targets and Selective Routes for the Development of New Antimalarial Agents Henry M. Staines* ,1 , J. Clive Ellory 1 and Kelly Chibale 2 1 University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK 2 Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa Abstract: The malaria parasite, Plasmodium falciparum, spends part of its complex life cycle within the red blood cells of a human host. During this time, the parasite alters the permeability of the red blood cell’s plasma membrane to allow the uptake of nutrients, the removal of “waste” and volume and ion regulation of the infected cell. The increased permeability is due to the induction of new permeability pathways (NPP), which are obvious chemotherapeutic antimalarial targets and/or selective routes for drugs, which target the internal parasite. This review covers our present understanding of the NPP, the methods used to screen for putative inhibitors of the NPP, the current repertoire of NPP inhibitors and the problems that need to be addressed to realise the potential of the NPP as antimalarial targets. In addition, the review will cover the use of the NPP as specific drug delivery routes. Keywords: Malaria, Channel, Anion, Antimalarial. 1. INTRODUCTION external medium for normal growth [4]. These must first cross the RBC plasma membrane before they are accessible to the parasite. In the case of glucose (the parasite’s primary energy source), the native glucose transporter (GLUT1) is capable of supplying the parasite’s requirements [5]. However, there is no native transport pathway for the vitamin, pantothenate (required by the parasite for the production of co-enzyme A). As the NPP are permeable to pantothenate [6], they are thought to aid nutrient uptake. As part of its life cycle, the malaria parasite, Plasmodium falciparum, invades the red blood cells (RBCs) of its human host. In so doing, the parasite passes through the host plasma membrane and, at the same time, surrounds its own plasma membrane with a second membrane called the parasitophorous vacuole membrane (PVM). Within the RBC, P. falciparum takes approximately 48 hours to mature, divide and release up to 32 new parasites (at a metabolic rate far in excess of that of the host RBC). Secondly, to produce energy (in the form of ATP), the parasite utilises glycolysis primarily. The major by-product of this process is lactate and this is potentially toxic to the parasite if left to accumulate. Besides a small degree of diffusion of the protonated from, the RBC has two native transport pathways for the removal of lactate (the anion exchanger, Band 3, and the monocarboxylate transporter). However, it has been calculated that these pathways are not capable of clearing parasite-derived lactate and so a third route (i.e. the NPP) is required for metabolite removal [7, 8]. Approximately 15 hours into this asexual reproductive phase, the permeability of the host RBC’s plasma membrane increases to a range of relatively low molecular weight solutes including sugars, amino acids, nucleosides and inorganic ions. This occurs due to the induction of new permeability pathways (NPP) by the internal parasite. It has yet to be clarified to which compartment the NPP lead. A simple sequential model of solute trafficking, as suggested by Desai [1], would predict that the NPP lead to the RBC cytosol but other models have been hypothesised including the localisation of the NPP to points of contact between the host plasma membrane and the, so called, tubovesicular membrane (a network of tubular membranes extending from the PVM) [2]. The latter would predict that the NPP lead to the compartment between the PVM and the parasite plasma membrane. The evidence behind these models and more contentious models are discussed in greater detail by Kirk [3]. Thirdly, the parasite obtains some of the amino acids it requires for protein production from digestion of the host RBC’s cytosol (predominantly haemoglobin). Only a relatively small proportion of the amino acids produced by this process are used by the parasite [9]. If left to accumulate, an amino acid concentration gradient would form, which would draw water into the infected cell and swell it (ultimately lysing the cell before the parasite has divided). The NPP have, therefore, been proposed to aid amino acid release and provide the parasite with a mechanism for regulating the volume of the infected RBC [10]. 1.1. Why Induce the NPP? Four reasons have been postulated for why the parasite induces the NPP. Firstly, the parasite has an essential requirement for the presence of several nutrients in the Finally, a RBC maintains a low Na + concentration within its cytosol compared with the external milieu. This inward Na + gradient can be used to facilitate the transport of solutes, against their own concentration gradients, across the cell membrane (known as secondary active transport due to the need for a primary active transport process to produce the *Address correspondence to this author at the University Laboratory of Physiology, Parks Road, Oxford OX1 3PT, UK; Tel: ++44 1865 285828; Fax: ++44 1865 272469; E-mail: henry.staines@physiol.ox.ac.uk 1386-2073/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.