5'-Phosphorylation Increases the Efficacy of Nucleoside Inhibitors of the DNA Repair Enzyme SNM1A.
DNA repair
SNM1A
nuclease inhibitors
nucleotides
zinc-binding group
Journal
ChemMedChem
ISSN: 1860-7187
Titre abrégé: ChemMedChem
Pays: Germany
ID NLM: 101259013
Informations de publication
Date de publication:
04 03 2022
04 03 2022
Historique:
revised:
07
12
2021
received:
15
09
2021
pubmed:
15
12
2021
medline:
3
5
2022
entrez:
14
12
2021
Statut:
ppublish
Résumé
Certain cancers exhibit upregulation of DNA interstrand crosslink repair pathways, which contributes to resistance to crosslinking chemotherapy drugs and poor prognoses. Inhibition of enzymes implicated in interstrand crosslink repair is therefore a promising strategy for improving the efficacy of cancer treatment. One such target enzyme is SNM1A, a zinc co-ordinating 5'-3' exonuclease. Previous studies have demonstrated the feasibility of inhibiting SNM1A using modified nucleosides appended with zinc-binding groups. In this work, we sought to develop more effective SNM1A inhibitors by exploiting interactions with the phosphate-binding pocket adjacent to the enzyme's active site, in addition to the catalytic zinc ions. A series of nucleoside derivatives bearing phosphate moieties at the 5'-position, as well as zinc-binding groups at the 3'-position, were prepared and tested in gel-electrophoresis and real-time fluorescence assays. As well as investigating novel zinc-binding groups, we found that incorporation of a 5'-phosphate dramatically increased the potency of the inhibitors.
Identifiants
pubmed: 34905656
doi: 10.1002/cmdc.202100603
doi:
Substances chimiques
Enzyme Inhibitors
0
Nucleosides
0
Phosphates
0
Exodeoxyribonucleases
EC 3.1.-
DNA Repair Enzymes
EC 6.5.1.-
Zinc
J41CSQ7QDS
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202100603Informations de copyright
© 2021 Wiley-VCH GmbH.
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