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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
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):
Doi: 10.3390/biom11010120
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- Co-authors Med Uni Graz
- Sánchez Murcia Pedro Alejandro
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- Abstract:
- 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.
- Find related publications in this database (Keywords)
- chemotherapy
- suicide gene therapy
- nucleoside analogues
- 2′
- -deoxyribosyltransferase
- structural bioinformatics
- molecular dynamics