Transporters that translocate nucleosides and structural similar drugs: structural requirements for substrate recognition

Abstract

Nucleoside transporters (NT) are integral membrane proteins implicated in the salvage of natural nucleobases and nucleosides for nucleic acid synthesis. These proteins also play a crucial role as carriers of nucleoside analogs used in anticancer and antiviral therapies. In fact, differential expression patterns of NT subtypes among tissues and individuals as well as the existence of genetic variants affect nucleoside-derived drug permeation, and consequently, their pharmacokinetic and cytotoxic properties. Thus, NT expression patterns may be effective predictive markers of therapeutic response. While the structures of NT proteins are yet to be solved, specific residues responsible for interaction with substrates and inhibitors have been identified, providing further insights into their structure-function relationship. In addition to transporter structural features, several experimental approaches have been used to identify the structural requirements of nucleosides for interaction with Concentrative Nucleoside Transporters and Equilibrative Nucleoside Transporters (SLC28 and SLC29 gene families, respectively). Pharmacophore models proposed for both protein families may prove suitable for optimizing drug design. Additional transporter proteins, including Organic Anion Transporters, Organic Cation Transporters (members of the SLC22 gene family), and Peptide Transporters (SLC15 gene family), have been implicated in the uptake of nucleoside-derived drugs, particularly those currently used in antiviral therapies. In this review, we focus on the pharmacological profiles of these transporter proteins, summarizing the documented studies covering structure-function and substrate structural requirement properties that determine drug-carrier interaction and efficient substrate translocation across the plasma membrane of target cells.