Sichuan Provincial Education Department Key Laboratory of Medicinal and Edible Plant Resources Development, College of Pharmacy, Chengdu University, Chengdu, China.
School of Marxism, Chengdu Vocational & Technical College of Industry, Chengdu, China.
Curr Protein Pept Sci. 2024;25(2):120-136. doi: 10.2174/1389203724666230905110952.
Membrane protein human concentrative nucleoside transporter 3 (hCNT3) can not only transport extracellular nucleosides into the cell but also transport various nucleoside-derived anticancer drugs to the focus of infection for therapeutic effects. Typical nucleoside anticancer drugs, including fludarabine, cladabine, decitabine, and clofarabine, are recognized by hCNT3 and then delivered to the lesion site for their therapeutic effects. hCNT3 is highly conserved during the evolution from lower to higher vertebrates, which contains scaffold and transport domains in structure and delivers substrates by coupling with Naand H ions in function. In the process of substrate delivery, the transport domain rises from the lower side of transmembrane 9 (TM9) in the inward conformation to the upper side of the outward conformation, accompanied by the collaborative motion of TM7b/ TM4b and hairpin 1b (HP1b)/ HP2b. With the report of a series of three-dimensional structures of homologous CNTs, the structural characteristics and biological functions of hCNT3 have attracted increasing attention from pharmacists and biologists. Our research group has also recently designed an anticancer lead compound with high hCNT3 transport potential based on the structure of 5-fluorouracil. In this work, the sequence evolution, conservation, molecular structure, cationic chelation, substrate recognition, elevator motion pattern and nucleoside derivative drugs of hCNT3 were reviewed, and the differences in hCNT3 transport mode and nucleoside anticancer drug modification were summarized, aiming to provide theoretical guidance for the subsequent molecular design of novel anticancer drugs targeting hCNT3.
膜蛋白人嘌呤核苷转运蛋白 3（hCNT3）不仅可以将细胞外核苷转运到细胞内，还可以将各种核苷衍生的抗癌药物转运到感染病灶部位发挥治疗作用。典型的核苷类抗癌药物，包括氟达拉滨、卡培他滨、地西他滨和克拉屈滨等，都被 hCNT3 识别，然后被递送到病变部位发挥治疗作用。hCNT3 在从低等到高等脊椎动物的进化过程中高度保守，其结构中包含支架和转运结构域，通过与 Na 和 H 离子偶联来输送底物。在底物输送过程中，转运结构域从内向构象的跨膜 9（TM9）的下侧上升到外向构象的上侧，同时伴随着 TM7b/TM4b 和发夹 1b（HP1b）/HP2b 的协同运动。随着一系列同源 CNT 三维结构的报道，hCNT3 的结构特征和生物学功能引起了药剂师和生物学家越来越多的关注。我们的研究小组还根据 5-氟尿嘧啶的结构设计了一种具有高 hCNT3 转运潜力的抗癌先导化合物。在这项工作中，综述了 hCNT3 的序列进化、保守性、分子结构、阳离子螯合、底物识别、提升运动模式和核苷衍生物药物，总结了 hCNT3 转运方式和核苷类抗癌药物修饰的差异，旨在为后续靶向 hCNT3 的新型抗癌药物的分子设计提供理论指导。
