Interaction of nucleoside inhibitors of HIV-1 reverse transcriptase with the concentrative nucleoside transporter-1 (SLC28A1).
Human concentrative nucleoside transporter-1 (hCNT1) (SLC28A1) is a widely expressed, high-affinity, pyrimidine-preferring, nucleoside transporter implicated in the uptake of naturally occurring pyrimidine nucleosides as well as a variety of derivatives used in anticancer treatment. Its putative role in the uptake of other pyrimidine nucleoside analogues with antiviral properties has not been studied in detail to date. Here, using a hCNT1 stably transfected cell line and the two-electrode voltage-clamp technique, we have assessed the interaction of selected pyrimidine-based antiviral drugs, inhibitors of HIV-1 reverse transcriptase such as zidovudine (AZT), stavudine (d4T), lamivudine (3TC) and zalcitabine (ddC), with hCNT1. hCNT1 transports AZT and d4T with low affinity, whereas 3TC and ddC are not translocated, the latter being able to bind the transporter protein. Selectivity appears to rely mostly upon the presence of a hydroxyl group in the 3'-position of the ribose ring. Thus, hCNT1 cannot be considered a broad-selectivity pyrimidine nucleoside carrier; in fact, very slight changes in substrate structure provoke a dramatic shift in selectivity.
Cano-Soldado
Pedro
P
Department de Bioquimica i Biologia Molecular, Universitat de Barcelona, Barcelona, Spain.
Lorráyoz
Ignacio M
IM
Molina-Arcas
Míriam
M
Casado
F Javier
FJ
Martinez-Picado
Javier
J
Lostao
M Pilar
MP
Pastor-Anglada
Marçal
M
D000818:Animals; D019380:Anti-HIV Agents / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D004347:Drug Interactions; D054303:HIV Reverse Transcriptase / Q000009:adverse effects*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D033703:Nucleoside Transport Proteins / Q000235:genetics / Q000378:metabolism*; D009865:Oocytes / Q000378:metabolism; D018408:Patch-Clamp Techniques; D018894:Reverse Transcriptase Inhibitors / Q000378:metabolism*; D014162:Transfection; D014982:Xenopus laevis / Q000254:growth & development
D019380:Anti-HIV Agents; D033703:Nucleoside Transport Proteins; D018894:Reverse Transcriptase Inhibitors; D054303:HIV Reverse Transcriptase