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Acosta, Javier Pérez, Elena Sánchez Murcia, Pedro A. Fillat, Cristina Fernández Lucas, Jesús 2024-10-17T15:26:42Z 2024-10-17T15:26:42Z 2021 Acosta J, Pérez E, Sánchez-Murcia PA, Fillat C, Fernández-Lucas J. Molecular Basis of NDT-Mediated Activation of Nucleoside-Based Prodrugs and Application in Suicide Gene Therapy. Biomolecules 2021;11:120. https://doi.org/10.3390/biom11010120. 10.3390/biom11010120 https://hdl.handle.net/20.500.14352/109083 2218-273X https://doi.org/10.3390/biom11010120 https://www.mdpi.com/2218-273X/11/1/120 Herein 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. eng http://creativecommons.org/licenses/by/4.0/ open access Attribution 4.0 International Molecular basis of NDT-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy journal article