Inhibition of DNA Glycosylases via Small Molecule Purine Analogs
Publication Date
December 09, 2013
Journal
PLOS ONE
Authors
Aaron C. Jacobs, Marcus J. Calkins, Ajit Jadhav, Dorjbal Dorjsuren, et al
Volume
8
Issue
12
Pages
e81667
DOI
https://dx.plos.org/10.1371/journal.pone.0081667
Publisher URL
http://journals.plos.org/plosone/article?id=10.1371%2Fjournal.pone.0081667
PubMed
http://www.ncbi.nlm.nih.gov/pubmed/24349107
PubMed Central
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3857224
Europe PMC
http://europepmc.org/abstract/MED/24349107
Web of Science
000328705200041
Scopus
84892573362
Mendeley
http://www.mendeley.com/research/inhibition-dna-glycosylases-via-small-molecule-purine-analogs
Events
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Mendeley | Further Information

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Scopus | Further Information

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Figshare

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  • {"files"=>["https://ndownloader.figshare.com/files/1308551"], "description"=>"<p>Design of oligonucleotide substrates.</p>", "links"=>[], "tags"=>["oligonucleotide"], "article_id"=>872518, "categories"=>["Biological Sciences"], "users"=>["Aaron C. Jacobs", "Marcus J. Calkins", "Ajit Jadhav", "Dorjbal Dorjsuren", "David Maloney", "Anton Simeonov", "Pawel Jaruga", "Miral Dizdaroglu", "Amanda K. McCullough", "R. Stephen Lloyd"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0081667.g001", "stats"=>{"downloads"=>1, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Design_of_oligonucleotide_substrates_/872518", "title"=>"Design of oligonucleotide substrates.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-09 03:51:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1308565"], "description"=>"<div><p>Following the formation of oxidatively-induced DNA damage, several DNA glycosylases are required to initiate repair of the base lesions that are formed. Recently, NEIL1 and other DNA glycosylases, including OGG1 and NTH1 were identified as potential targets in combination chemotherapeutic strategies. The potential therapeutic benefit for the inhibition of DNA glycosylases was validated by demonstrating synthetic lethality with drugs that are commonly used to limit DNA replication through dNTP pool depletion via inhibition of thymidylate synthetase and dihydrofolate reductase. Additionally, NEIL1-associated synthetic lethality has been achieved in combination with Fanconi anemia, group G. As a prelude to the development of strategies to exploit the potential benefits of DNA glycosylase inhibition, it was necessary to develop a reliable high-throughput screening protocol for this class of enzymes. Using NEIL1 as the proof-of-principle glycosylase, a fluorescence-based assay was developed that utilizes incision of site-specifically modified oligodeoxynucleotides to detect enzymatic activity. This assay was miniaturized to a 1536-well format and used to screen small molecule libraries for inhibitors of the combined glycosylase/AP lyase activities. Among the top hits of these screens were several purine analogs, whose postulated presence in the active site of NEIL1 was consistent with the paradigm of NEIL1 recognition and excision of damaged purines. Although a subset of these small molecules could inhibit other DNA glycosylases that excise oxidatively-induced DNA adducts, they could not inhibit a pyrimidine dimer-specific glycosylase.</p></div>", "links"=>[], "tags"=>["dna", "glycosylases", "purine"], "article_id"=>872532, "categories"=>["Biological Sciences"], "users"=>["Aaron C. Jacobs", "Marcus J. Calkins", "Ajit Jadhav", "Dorjbal Dorjsuren", "David Maloney", "Anton Simeonov", "Pawel Jaruga", "Miral Dizdaroglu", "Amanda K. McCullough", "R. Stephen Lloyd"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0081667", "stats"=>{"downloads"=>3, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_DNA_Glycosylases_via_Small_Molecule_Purine_Analogs_/872532", "title"=>"Inhibition of DNA Glycosylases via Small Molecule Purine Analogs", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-12-09 03:51:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1308562"], "description"=>"<p>Specificity of various purine inhibitors for different glycosylase-substrate combinations as determined by IC<sub>50</sub> value.</p>", "links"=>[], "tags"=>["purine", "inhibitors", "glycosylase-substrate", "combinations"], "article_id"=>872529, "categories"=>["Biological Sciences"], "users"=>["Aaron C. Jacobs", "Marcus J. Calkins", "Ajit Jadhav", "Dorjbal Dorjsuren", "David Maloney", "Anton Simeonov", "Pawel Jaruga", "Miral Dizdaroglu", "Amanda K. McCullough", "R. Stephen Lloyd"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0081667.g009", "stats"=>{"downloads"=>1, "page_views"=>5, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Specificity_of_various_purine_inhibitors_for_different_glycosylase_substrate_combinations_as_determined_by_IC_50_value_/872529", "title"=>"Specificity of various purine inhibitors for different glycosylase-substrate combinations as determined by IC<sub>50</sub> value.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-09 03:51:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1308561"], "description"=>"<p>Levels of A) FapyGua and B) FapyAde released from γ-irradiated DNA by NEIL1 in the absence or presence of various inhibitors.</p>", "links"=>[], "tags"=>["neil1", "inhibition"], "article_id"=>872528, "categories"=>["Biological Sciences"], "users"=>["Aaron C. Jacobs", "Marcus J. Calkins", "Ajit Jadhav", "Dorjbal Dorjsuren", "David Maloney", "Anton Simeonov", "Pawel Jaruga", "Miral Dizdaroglu", "Amanda K. McCullough", "R. Stephen Lloyd"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0081667.g008", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Determination_of_NEIL1_inhibition_by_GS_MS_MS_/872528", "title"=>"Determination of NEIL1 inhibition by GS-MS/MS.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-09 03:51:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1308559"], "description"=>"<p>A) CGP-74514A, B) P2, C) P6, D) P7, E) P8 compared to no inhibitor (gray squares) or no enzyme (gray triangles). F) IC<sub>50</sub> values determined during validation of HTS.</p>", "links"=>[], "tags"=>["neil1", "10", "concentrations"], "article_id"=>872526, "categories"=>["Biological Sciences"], "users"=>["Aaron C. Jacobs", "Marcus J. Calkins", "Ajit Jadhav", "Dorjbal Dorjsuren", "David Maloney", "Anton Simeonov", "Pawel Jaruga", "Miral Dizdaroglu", "Amanda K. McCullough", "R. Stephen Lloyd"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0081667.g007", "stats"=>{"downloads"=>1, "page_views"=>7, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inhibition_of_NEIL1_activity_with_10_181_M_concentrations_of_select_compounds_/872526", "title"=>"Inhibition of NEIL1 activity with 10 µM concentrations of select compounds.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-09 03:51:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1308556"], "description"=>"<p>A) Inhibition of NEIL1 activity in the HTS of the LOPAC library by aurintricarboxylic acid (squares), ellipticine (triangles), and CGP-74514A (circles). B) Inhibition of NEIL1 activity by purine analogs P2 (circles), P6 (squares), P7 (triangles), and P8 (inverted triangles).</p>", "links"=>[], "tags"=>[], "article_id"=>872523, "categories"=>["Biological Sciences"], "users"=>["Aaron C. Jacobs", "Marcus J. Calkins", "Ajit Jadhav", "Dorjbal Dorjsuren", "David Maloney", "Anton Simeonov", "Pawel Jaruga", "Miral Dizdaroglu", "Amanda K. McCullough", "R. Stephen Lloyd"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0081667.g005", "stats"=>{"downloads"=>1, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_High_throughput_screen_of_selected_small_molecule_libraries_/872523", "title"=>"High-throughput screen of selected small molecule libraries.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-09 03:51:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1308555"], "description"=>"<p>A) Fluorescent signal observed when Sp/Gh substrate was incubated with various concentrations of NEIL1. B) Cleavage observed by gel electrophoresis when Sp/Gh substrate was incubated with various concentrations of NEIL1.</p>", "links"=>[], "tags"=>["substrate"], "article_id"=>872522, "categories"=>["Biological Sciences"], "users"=>["Aaron C. Jacobs", "Marcus J. Calkins", "Ajit Jadhav", "Dorjbal Dorjsuren", "David Maloney", "Anton Simeonov", "Pawel Jaruga", "Miral Dizdaroglu", "Amanda K. McCullough", "R. Stephen Lloyd"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0081667.g004", "stats"=>{"downloads"=>2, "page_views"=>28, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Cleavage_of_Sp_Gh_substrate_by_NEIL1_/872522", "title"=>"Cleavage of Sp/Gh substrate by NEIL1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-09 03:51:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1308564"], "description"=>"<p>A) Inhibition of the lyase activity of various bifunctional glycosylases with purine analogs. B) DNA ladder gel shift assay with addition of various inhibitors or ellipticine control.</p>", "links"=>[], "tags"=>["inhibition"], "article_id"=>872531, "categories"=>["Biological Sciences"], "users"=>["Aaron C. Jacobs", "Marcus J. Calkins", "Ajit Jadhav", "Dorjbal Dorjsuren", "David Maloney", "Anton Simeonov", "Pawel Jaruga", "Miral Dizdaroglu", "Amanda K. McCullough", "R. Stephen Lloyd"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0081667.g010", "stats"=>{"downloads"=>1, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Specificity_of_the_inhibition_of_NEIL1_/872531", "title"=>"Specificity of the inhibition of NEIL1.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-12-09 03:51:57"}

PMC Usage Stats | Further Information

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Relative Metric

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