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 Na+ and 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.