New Malaria Chemotherapy Developed by Utilization of a Unique Parasite Transport System

Annette   M.   Gero; Catherine   G.   Dunn; David   M.   Brown; Kirupa      Pulenthiran; Elena   L.   Gorovits; Tomas      Bakos; Alexander   L.   Weis

doi:10.2174/1381612033455233

Abstract

During its development in the host red cell, the human malarial parasite causes profound alteration in the permeability of the host cell membrane. These membrane transport systems(s) play a role in the development of the intra-erythrocytic parasite in its need to take up solutes and nutrients from the extracellular medium and the disposal of metabolic wastes. Importantly, the properties of these parasite induced transport systems are significantly different from those in normal human cells. Hence, such systems are of considerable interest for their potential use in anti-malarial chemotherapy, both by (i) inhibiting the transport and hence depriving the parasite of nutrients essential for its development, or (ii) by designing cytotoxic drugs which selectively enter the parasite through these induced transporter routes and hence cannot enter normal mammalian cells. Since our discovery that optical isomers of nucleosides (such as Ladenosine or L- thymidine) were selectively transported into malaria infected cells through the induced transporter, L-nucleoside drug “carriers” were actively synthesized as potentially new therapeutic agents. The compounds are dinucleoside phosphate dimers, where each ”carrier“ (a L-nucleoside) has been conjugated to known anti-malarial agents, such as 5-fluro-uridine through the 3 and 5-OH and a phosphate group. A very large series of these drugs have been synthesized with varying conjugations. The dimers are extremely toxic against malaria and experimental evidence has confirmed that they are incapable of entering normal mammalian cells. This review discusses their mechanism of action and potential as new anti-malarial chemotherapy as well as the role played by the membrane transport system of malaria infected cells as a target for malaria chemotherapy.

Keywords: Malaria, Chemotherapy, isomers, fluro-uridine, anti-malarial agents, mammalian cells, L- thymidine

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