ArticleJournal of the American Chemical Society2005
Uracil-directed ligand tethering: an efficient strategy for uracil DNA glycosylase (UNG) inhibitor development.
Article in Journal of the American Chemical Society, 2005. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 67 citations in OpenAlex.
- Article
- Structural and Functional Insights into UDGs.Protein and peptide letters · 2025Review
- Energy Landscapes for Base-Flipping in a Model DNA Duplex.The journal of physical chemistry. B · 2022Article
- A New Class of Uracil-DNA Glycosylase Inhibitors Active against Human and Vaccinia Virus Enzyme.Molecules (Basel, Switzerland) · 2021Article
- An effective human uracil-DNA glycosylase inhibitor targets the open pre-catalytic active site conformation.Progress in biophysics and molecular biology · 2021Article
- Viruses with U-DNA: New Avenues for Biotechnology.Viruses · 2021Review
- Focus on DNA Glycosylases-A Set of Tightly Regulated Enzymes with a High Potential as Anticancer Drug Targets.International journal of molecular sciences · 2020Review
- Base excision repair and its implications to cancer therapy.Essays in biochemistry · 2020Review
- Inhibitors of DNA Glycosylases as Prospective Drugs.International journal of molecular sciences · 2020Review
- The Essential Co-Option of Uracil-DNA Glycosylases by Herpesviruses Invites Novel Antiviral Design.Microorganisms · 2020Review
- A robust photoluminescence screening assay identifies uracil-DNA glycosylase inhibitors against prostate cancer.Chemical science · 2020Article
- Design, synthesis, crystal structure and fungicidal activity of (MedChemComm · 2017Article
- Hydroxybenzaldoximes Are D-GAP-Competitive Inhibitors of E. coli 1-Deoxy-D-Xylulose-5-Phosphate Synthase.Chembiochem : a European journal of chemical biology · 2015Article
- A High-Throughput Enzyme-Coupled Assay for SAMHD1 dNTPase.Journal of biomolecular screening · 2015Article
- Synthetic derivatives of the SUMO consensus sequence provide a basis for improved substrate recognition.Bioorganic & medicinal chemistry letters · 2015Article
- Identification of an Atg8-Atg3 protein-protein interaction inhibitor from the medicines for Malaria Venture Malaria Box active in blood and liver stage Plasmodium falciparum parasites.Journal of medicinal chemistry · 2014Article
- Irreversible inhibition of DNA polymerase β by small-molecule mimics of a DNA lesion.Journal of the American Chemical Society · 2014Article
- Vpr expression abolishes the capacity of HIV-1 infected cells to repair uracilated DNA.Nucleic acids research · 2014Article
- Article
- Timing facilitated site transfer of an enzyme on DNA.Nature chemical biology · 2012Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
Uracil DNA glycosylase (UNG) is an important DNA repair enzyme that recognizes and excises uracil bases in DNA using an extrahelical recognition mechanism. It is emerging as a desirable target for small-molecule inhibitors given its key role in a wide range of biological processes including the generation of antibody diversity, DNA replication in a number of viruses, and the formation of DNA strand breaks during anticancer drug therapy. To accelerate the discovery of inhibitors of UNG we have developed a uracil-directed ligand tethering strategy. In this efficient approach, a uracil aldehyde ligand is tethered via alkyloxyamine linker chemistry to a diverse array of aldehyde binding elements. Thus, the mechanism of extrahelical recognition of the uracil ligand is exploited to target the UNG active site, and alkyloxyamine linker tethering is used to randomly explore peripheral binding pockets. Since no compound purification is required, this approach rapidly identified the first small-molecule inhibitors of human UNG with micromolar to submicromolar binding affinities. In a surprising result, these uracil-based ligands are found not only to bind to the active site but also to bind to a second uncompetitive site. The weaker uncompetitive site suggests the existence of a transient binding site for uracil during the multistep extrahelical recognition mechanism. This very general inhibitor design strategy can be easily adapted to target other enzymes that recognize nucleobases, including other DNA repair enzymes that recognize other types of extrahelical DNA bases.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.