Molecular basis of NDT-mediated activation of nucleoside-based prodrugs and application in suicide gene therapy

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 (d...

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Bibliographic Details
Authors: Acosta, Javier, Pérez, Elena, Sánchez Murcia, Pedro A., Fillat, Cristina, Fernández Lucas, Jesús
Format: article
Publication Date:2021
Country:España
Institution:Universidad Complutense de Madrid (UCM)
Repository:Docta Complutense
Language:English
OAI Identifier:oai:docta.ucm.es:20.500.14352/109083
Online Access:https://hdl.handle.net/20.500.14352/109083
Access Level:Open access
Keyword:577.2
616-006
615.3
Chemotherapy
Suicide gene therapy
Nucleoside analogues
2′-deoxyribosyltransferase
Structural bioinformatics
Molecular dynamics
Biología molecular (Biología)
Oncología
Farmacología (Medicina)
2302.21 Biología Molecular
3201.01 Oncología
2302.22 Farmacología Molecular
Description
Summary: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.

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