Nucleoside transporter proteins: emerging targets for drug discovery

Abstract

Nucleosides are central salvage metabolites and, as precursors of nucleotides, play an essential role in intermediary metabolism and biosynthesis, as well as signal transduction through interaction with purinergic receptors. Nucleoside analogues are used to treat haematological malignancies, certain solid tumours and many viral diseases. Because most nucleosides are relatively hydrophilic molecules, the presence of specialised transporter proteins in plasma membranes is essential for cellular uptake. Nucleoside transport is mediated by either bi-directional equilibrative processes, driven by chemical gradients, or inwardly directed concentrative processes, driven by sodium gradients. Recent advances in the identification of nucleoside transporter proteins from humans and lower organisms, using molecular cloning and functional expression of cDNAs, have transformed our understanding of nucleoside transport processes. Most of the nucleoside transporters identified thus far are members of two previously unrecognised and evolutionarily old protein families, the equilibrative nucleoside transporters (ENTs) and concentrative nucleoside transporters (CNTs), whose biological functions have not been fully determined. In humans, the ENTs exhibit broad permeant selectivities and are widely distributed among different cell types, whereas the CNTs exhibit more restricted permeant selectivities and are found primarily in specialised cell types. Members of both families have been observed in neoplastic cells. This review focuses on the nucleoside transporter proteins of humans and rodents that have become known through molecular cloning and functional expression of their cDNAs, and describes relationships with the transporters of lower organisms. Recent advances in functional production of recombinant nucleoside transporters in model expression systems will allow the development of new therapeutic strategies to improve the efficacy and selectivity of nucleoside drugs in therapy of cancer, as well as viral and parasitic diseases.

• adenosine
• antimetabolites
• antiviral chemotherapy
• cancer chemotherapy
• membrane transporter proteins
• nucleoside transport
• nucleotide metabolism
• parasitic disease
• purinergic receptors
• uridine