The translocation of nucleosides across cellular membranes requires a specific category of integral membrane proteins,known as nucleoside transporters.These proteins are crucial for the absorption of endogenous nucleo...The translocation of nucleosides across cellular membranes requires a specific category of integral membrane proteins,known as nucleoside transporters.These proteins are crucial for the absorption of endogenous nucleosides as well as nucleoside-derived pharmaceuticals,including antineoplastic drugs.This research examined the comparative dynamic behavior of[Pt(dien)(N7-dGuo)]^(2+)(1),cis-[Pt(NH_(3))_(2)Cl(N7-dGuo)]^(+)(2),and cis-[Pt(NH_(3))_(2)(H_(2)O)(N7-dGuo)]^(2+)(3)(where dien=diethylenetriamine and dGuo=5’-(2’-deoxy)-guanosine)platinated nucleosides in the human concentrative nucleoside transporter type 3(hCNT3),utilizing molecular dynamics(MD)simulations.The membrane protein hCNT3 is involved in the cellular absorption of numerous therapeutic nucleoside derivatives used in the treatment of both viral infections and malignancies.These simulations facilitated the characterization of the ligand-binding site,underscoring the critical role of the transmembrane domain TM9 in promoting nucleoside translocation across the membrane and in determining the interaction of certain platinated nucleosides within the transporter channel.Overall,this work underscores the potential of platinum-based modifications to enhance antitumor therapies based on nucleoside analogues by synergistically targeting hCNT transporters,metabolic pathways of natural nucleosides,and DNA functionality.Notably,the latter interactions,in the case of complexes 2 and 3,could also produce the classical 1,2-intrastrand cross-link lesions with DNA,which are considered responsible for the antitumor activity of cisplatin and analogous complexes.These considerations could lay the groundwork for new strategies aimed at developing antitumor drugs characterized by enhanced antitumor activity,selectivity for tumor cells,and reduced systemic side effects.展开更多
基金Financial support from Dipartimento di Chimica e Tecnologie Chimiche,Universitàdella Calabria,is acknowledgedfunded by ENEA,the Italian National Agency for New Technologies,Energy and Sustainable Economic Developmentby Italian and European research programs。
文摘The translocation of nucleosides across cellular membranes requires a specific category of integral membrane proteins,known as nucleoside transporters.These proteins are crucial for the absorption of endogenous nucleosides as well as nucleoside-derived pharmaceuticals,including antineoplastic drugs.This research examined the comparative dynamic behavior of[Pt(dien)(N7-dGuo)]^(2+)(1),cis-[Pt(NH_(3))_(2)Cl(N7-dGuo)]^(+)(2),and cis-[Pt(NH_(3))_(2)(H_(2)O)(N7-dGuo)]^(2+)(3)(where dien=diethylenetriamine and dGuo=5’-(2’-deoxy)-guanosine)platinated nucleosides in the human concentrative nucleoside transporter type 3(hCNT3),utilizing molecular dynamics(MD)simulations.The membrane protein hCNT3 is involved in the cellular absorption of numerous therapeutic nucleoside derivatives used in the treatment of both viral infections and malignancies.These simulations facilitated the characterization of the ligand-binding site,underscoring the critical role of the transmembrane domain TM9 in promoting nucleoside translocation across the membrane and in determining the interaction of certain platinated nucleosides within the transporter channel.Overall,this work underscores the potential of platinum-based modifications to enhance antitumor therapies based on nucleoside analogues by synergistically targeting hCNT transporters,metabolic pathways of natural nucleosides,and DNA functionality.Notably,the latter interactions,in the case of complexes 2 and 3,could also produce the classical 1,2-intrastrand cross-link lesions with DNA,which are considered responsible for the antitumor activity of cisplatin and analogous complexes.These considerations could lay the groundwork for new strategies aimed at developing antitumor drugs characterized by enhanced antitumor activity,selectivity for tumor cells,and reduced systemic side effects.
