Affiliation:
1. School of Chemistry and Trinity Biomedical Sciences Institute Trinity College Dublin The University of Dublin Dublin 2 D02 R590 Ireland
2. Department of Chemistry University of Oxford Mansfield Road OX1 3TA Oxford UK
Abstract
AbstractWe report a two‐step validation approach to evaluate the suitability of metal‐binding groups for targeting DNA damage‐repair metalloenzymes using model enzyme SNM1A. A fragment‐based screening approach was first used to identify metal‐binding fragments suitable for targeting the enzyme. Effective fragments were then incorporated into oligonucleotides using the copper‐catalysed azide–alkyne cycloaddition reaction. These modified oligonucleotides were recognised by SNM1A at >1000‐fold lower concentrations than their fragment counterparts. The exonuclease SNM1A is a key enzyme involved in the repair of interstrand crosslinks, a highly cytotoxic form of DNA damage. However, SNM1A and other enzymes of this class are poorly understood, as there is a lack of tools available to facilitate their study. Our novel approach of incorporating functional fragments into oligonucleotides is broadly applicable to generating modified oligonucleotide structures with high affinity for DNA damage‐repair enzymes.
Subject
Organic Chemistry,Molecular Biology,Molecular Medicine,Biochemistry
Cited by
1 articles.
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