Departament de Bioquímica i Biologia Molecular, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona and CIBER EHD, Barcelona, Spain.
Med Res Rev. 2012 Mar;32(2):428-57. doi: 10.1002/med.20221. Epub 2011 Feb 1.
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.
核苷转运蛋白（NTs）是参与核酸合成中天然碱基和核苷回收的完整膜蛋白。这些蛋白还作为用于抗癌和抗病毒治疗的核苷类似物的载体，起着至关重要的作用。事实上，NT 亚型在组织和个体中的差异表达模式以及遗传变异的存在会影响核苷衍生药物的渗透，从而影响其药代动力学和细胞毒性特性。因此，NT 表达模式可能是治疗反应的有效预测标志物。虽然 NT 蛋白的结构尚未解决，但已经确定了与底物和抑制剂相互作用的特定残基，这为它们的结构-功能关系提供了进一步的见解。除了转运蛋白的结构特征外，还使用了几种实验方法来确定核苷与协同核苷转运蛋白（SLC28 基因家族）和平衡核苷转运蛋白（SLC29 基因家族）相互作用的结构要求。为这两个蛋白家族提出的药效团模型可能适合于优化药物设计。其他转运蛋白，包括有机阴离子转运蛋白、有机阳离子转运蛋白（SLC22 基因家族成员）和肽转运蛋白（SLC15 基因家族），已被牵涉到核苷衍生药物的摄取中，特别是那些目前用于抗病毒治疗的药物。在这篇综述中，我们重点介绍了这些转运蛋白的药理学特征，总结了涵盖结构-功能和底物结构要求特性的已有研究，这些特性决定了药物-载体相互作用和有效底物跨靶细胞质膜的转运。
