Acosta Bueno, JavierPérez Izquierdo, ElenaSánchez Murcia, Pedro AlejandroFillat Fonts, CristinaFernández Lucas, Jesús2022-04-262022-04-262021Acosta, J., Pérez, E., Sánchez-Murcia, P. A., Fillat, C., & Fernández-Lucas, J. (2021). Molecular Basis of NDT-Mediated Activation of Nucleoside-Based Prodrugs and Application in Suicide Gene Therapy. Biomolecules, 11(1), 120. https://doi.org/10.3390/biom110101202218-273Xhttp://hdl.handle.net/11268/11139Herein we report the first proof for the application of type II 2′-deoxyribosyltransferase from Lactobacillus delbrueckii (LdNDT) in suicide gene therapy for cancer treatment. To this end, we first confirm the hydrolytic ability of LdNDT over the nucleoside-based prodrugs 2′-deoxy-5-fluorouridine (dFUrd), 2′-deoxy-2-fluoroadenosine (dFAdo), and 2′-deoxy-6-methylpurine riboside (d6MetPRib). Such activity was significantly increased (up to 30-fold) in the presence of an acceptor nucleobase. To shed light on the strong nucleobase dependence for enzymatic activity, different molecular dynamics simulations were carried out. Finally, as a proof of concept, we tested the LdNDT/dFAdo system in human cervical cancer (HeLa) cells. Interestingly, LdNDT/dFAdo showed a pronounced reduction in cellular viability with inhibitory concentrations in the low micromolar range. These results open up future opportunities for the clinical implementation of nucleoside 2′-deoxyribosyltransferases (NDTs) in cancer treatment.spaAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/Quimioterapiajournal article10.3390/biom11010120open accessBiología molecularCáncerTratamiento médico