Towards the enzymatic synthesis of phosphorothioate containing LNA oligonucleotides.

DNA-Directed DNA Polymerase / metabolism Nucleic Acid Conformation Phosphorothioate Oligonucleotides / biosynthesis
Locked nucleic acids Modified nucleotides Phosphorothioates Polymerase synthesis Terminal deoxynucleotidyl transferase (TdT)

Journal

Bioorganic & medicinal chemistry letters
ISSN: 1464-3405
Titre abrégé: Bioorg Med Chem Lett
Pays: England
ID NLM: 9107377

Informations de publication

Date de publication:
15 09 2021
Historique:
received: 21 05 2021
revised: 24 06 2021
accepted: 28 06 2021
pubmed: 5 7 2021
medline: 5 1 2022
entrez: 4 7 2021
Statut: ppublish

Résumé

Therapeutic oligonucleotides require the addition of multiple chemical modifications to the nucleosidic scaffold in order to improve their drug delivery efficiency, cell penetration capacity, biological stability, and pharmacokinetic properties. This chemical modification pattern is often accompanied by a synthetic burden and by limitations in sequence length. Here, we have synthesized a nucleoside triphosphate analog bearing two simultaneous modifications at the level of the sugar (LNA) and the backbone (thiophosphate) and have tested its compatibility with enzymatic DNA synthesis which could abrogate some of these synthetic limitations. While this novel analog is not as well tolerated by polymerases compared to the corresponding α-thio-dTTP or LNA-TTP, α -thio-LNA-TTP can readily be used for enzymatic synthesis on universal templates for the introduction of phosphorothioated LNA nucleotides.

Identifiants

DOI: 10.1016/j.bmcl.2021.128242 PMID: 34217829
pubmed: 34217829
pii: S0960-894X(21)00469-8
doi: 10.1016/j.bmcl.2021.128242
pii:
doi:

Substances chimiques

Phosphorothioate Oligonucleotides 0
DNA-Directed DNA Polymerase EC 2.7.7.7

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

128242

Informations de copyright

Copyright © 2021 Elsevier Ltd. All rights reserved.

Auteurs

Marie Flamme (M)

Institut Pasteur, Department of Structural Biology and Chemistry, Laboratory for Bioorganic Chemistry of Nucleic Acids, CNRS UMR3523, 28, rue du Docteur Roux, 75724 Paris Cedex 15, France.

Steven Hanlon (S)

Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.

Hans Iding (H)

Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.

Kurt Puentener (K)

Department of Process Chemistry & Catalysis, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.

Filippo Sladojevich (F)

Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070 Basel, Switzerland.

Marcel Hollenstein (M)

Institut Pasteur, Department of Structural Biology and Chemistry, Laboratory for Bioorganic Chemistry of Nucleic Acids, CNRS UMR3523, 28, rue du Docteur Roux, 75724 Paris Cedex 15, France. Electronic address: marcel.hollenstein@pasteur.fr.

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Classifications MeSH

questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › DNA nucleotidyltransferases › DNA-directed DNA polymerase › Towards the enzymatic synthesis of...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Conformation d'acide nucléique › Towards the enzymatic synthesis of...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Nucléotides › Polynucléotides › Oligonucléotides › Oligonucléotides phosphorothioates › Towards the enzymatic synthesis of...