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Article

Molecular Basis of NDT-Mediated Activation of Nucleoside-Based Prodrugs and Application in Suicide Gene Therapy

1
Applied Biotechnology Group, European University of Madrid, c/ Tajo s/n, Villaviciosa de Odón, 28670 Madrid, Spain
2
Division of Physiological Chemistry, Otto-Loewi Research Center, Medical University of Graz, Neue Stiftingtalstraße 6/III, A-8010 Graz, Austria
3
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
4
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 08036 Barcelona, Spain
5
Grupo de Investigación en Ciencias Naturales y Exactas, GICNEX, Universidad de la Costa, CUC, Calle 58 # 55-66 Barranquilla, Colombia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Biomolecules 2021, 11(1), 120; https://doi.org/10.3390/biom11010120
Received: 29 December 2020 / Revised: 11 January 2021 / Accepted: 13 January 2021 / Published: 18 January 2021
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. View Full-Text
Keywords: chemotherapy; suicide gene therapy; nucleoside analogues; 2′-deoxyribosyltransferase; structural bioinformatics; molecular dynamics chemotherapy; suicide gene therapy; nucleoside analogues; 2′-deoxyribosyltransferase; structural bioinformatics; molecular dynamics
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MDPI and ACS Style

Acosta, J.; Pérez, E.; Sánchez-Murcia, P.A.; 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

AMA Style

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(1):120. https://doi.org/10.3390/biom11010120

Chicago/Turabian Style

Acosta, Javier, Elena Pérez, Pedro A. Sánchez-Murcia, Cristina Fillat, and Jesús Fernández-Lucas. 2021. "Molecular Basis of NDT-Mediated Activation of Nucleoside-Based Prodrugs and Application in Suicide Gene Therapy" Biomolecules 11, no. 1: 120. https://doi.org/10.3390/biom11010120

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