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Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.

The beta sub( 2)-adrenergic receptor ( beta sub( 2)AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known beta -adrenergic receptor drugs target the orth... Full description

Journal Title: Proceedings of the National Academy of Sciences of the United States of America February 14, 2017, Vol.114(7), pp.1708-1713
Main Author: Ahn, Seungkirl
Other Authors: Kahsai, Alem W , Pani, Biswaranjan , Wang, Qin-Ting , Zhao, Shuai , Wall, Alissa L , Strachan, Ryan T , Staus, Dean P , Wingler, Laura M , Sun, Lillian D , Sinnaeve, Justine , Choi, Minjung , Cho, Ted , Xu, Thomas T , Hansen, Gwenn M , Burnett, Michael B , Lamerdin, Jane E , Bassoni, Daniel L , Gavino, Bryant J , Husemoen
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
ID: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1620645114
Link: http://search.proquest.com/docview/1862760728/?pq-origsite=primo
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title: Allosteric "beta-blocker" isolated from a DNA-encoded small molecule library.
format: Article
creator:
  • Ahn, Seungkirl
  • Kahsai, Alem W
  • Pani, Biswaranjan
  • Wang, Qin-Ting
  • Zhao, Shuai
  • Wall, Alissa L
  • Strachan, Ryan T
  • Staus, Dean P
  • Wingler, Laura M
  • Sun, Lillian D
  • Sinnaeve, Justine
  • Choi, Minjung
  • Cho, Ted
  • Xu, Thomas T
  • Hansen, Gwenn M
  • Burnett, Michael B
  • Lamerdin, Jane E
  • Bassoni, Daniel L
  • Gavino, Bryant J
  • Husemoen
subjects:
  • Adrenergic Beta-Antagonists–Chemistry
  • Animals–Metabolism
  • Binding Sites–Pharmacology
  • Binding, Competitive–Genetics
  • DNA–Drug Effects
  • High-Throughput Screening Assays–Genetics
  • Humans–Methods
  • Ligands–Genetics
  • Molecular Structure–Metabolism
  • Mutation–Chemistry
  • Receptors, Adrenergic, Beta-2–Metabolism
  • Sf9 Cells–Pharmacology
  • Small Molecule Libraries–Pharmacology
  • Spodoptera–Pharmacology
  • Adrenergic Beta-Antagonists
  • Ligands
  • Receptors, Adrenergic, Beta-2
  • Small Molecule Libraries
  • DNA
  • DNA-Encoded Small-Molecule Library
ispartof: Proceedings of the National Academy of Sciences of the United States of America, February 14, 2017, Vol.114(7), pp.1708-1713
description: The beta sub( 2)-adrenergic receptor ( beta sub( 2)AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known beta -adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human beta sub( 2)AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2 - yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide ] , exhibiting a unique chemotype and low micromolar affinity for the beta sub( 2)AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the beta sub( 2)AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the beta sub( 2)AR. In cell-signaling studies, 15 inhibits cAMP production through the beta sub( 2)AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits beta -arrestin recruitment to the activated beta sub( 2)AR. This study presents an allosteric small-molecule ligand for the beta sub( 2)AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.
language: eng
source:
identifier: E-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1620645114
fulltext: fulltext
issn:
  • 10916490
  • 1091-6490
url: Link


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titleAllosteric "beta-blocker" isolated from a DNA-encoded small molecule library.
creatorAhn, Seungkirl ; Kahsai, Alem W ; Pani, Biswaranjan ; Wang, Qin-Ting ; Zhao, Shuai ; Wall, Alissa L ; Strachan, Ryan T ; Staus, Dean P ; Wingler, Laura M ; Sun, Lillian D ; Sinnaeve, Justine ; Choi, Minjung ; Cho, Ted ; Xu, Thomas T ; Hansen, Gwenn M ; Burnett, Michael B ; Lamerdin, Jane E ; Bassoni, Daniel L ; Gavino, Bryant J ; Husemoen
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ispartofProceedings of the National Academy of Sciences of the United States of America, February 14, 2017, Vol.114(7), pp.1708-1713
identifierE-ISSN: 1091-6490 ; DOI: 10.1073/pnas.1620645114
subjectAdrenergic Beta-Antagonists–Chemistry ; Animals–Metabolism ; Binding Sites–Pharmacology ; Binding, Competitive–Genetics ; DNA–Drug Effects ; High-Throughput Screening Assays–Genetics ; Humans–Methods ; Ligands–Genetics ; Molecular Structure–Metabolism ; Mutation–Chemistry ; Receptors, Adrenergic, Beta-2–Metabolism ; Sf9 Cells–Pharmacology ; Small Molecule Libraries–Pharmacology ; Spodoptera–Pharmacology ; Adrenergic Beta-Antagonists ; Ligands ; Receptors, Adrenergic, Beta-2 ; Small Molecule Libraries ; DNA ; DNA-Encoded Small-Molecule Library
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descriptionThe beta sub( 2)-adrenergic receptor ( beta sub( 2)AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known beta -adrenergic receptor drugs target the orthosteric binding site of the receptor, we set out to isolate allosteric ligands for this receptor by panning DNA-encoded small-molecule libraries comprising 190 million distinct compounds against purified human beta sub( 2)AR. Here, we report the discovery of a small-molecule negative allosteric modulator (antagonist), compound 15 [([4-((2S)-3-(((S)-3-(3-bromophenyl)-1-(methylamino)-1-oxopropan-2 - yl)amino)-2-(2-cyclohexyl-2-phenylacetamido)-3-oxopropyl)benzamide ] , exhibiting a unique chemotype and low micromolar affinity for the beta sub( 2)AR. Binding of 15 to the receptor cooperatively enhances orthosteric inverse agonist binding while negatively modulating binding of orthosteric agonists. Studies with a specific antibody that binds to an intracellular region of the beta sub( 2)AR suggest that 15 binds in proximity to the G-protein binding site on the cytosolic surface of the beta sub( 2)AR. In cell-signaling studies, 15 inhibits cAMP production through the beta sub( 2)AR, but not that mediated by other Gs-coupled receptors. Compound 15 also similarly inhibits beta -arrestin recruitment to the activated beta sub( 2)AR. This study presents an allosteric small-molecule ligand for the beta sub( 2)AR and introduces a broadly applicable method for screening DNA-encoded small-molecule libraries against purified GPCR targets. Importantly, such an approach could facilitate the discovery of GPCR drugs with tailored allosteric effects.
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titleAllosteric "beta-blocker" isolated from a DNA-encoded small molecule library.
authorAhn, Seungkirl ; Kahsai, Alem W ; Pani, Biswaranjan ; Wang, Qin-Ting ; Zhao, Shuai ; Wall, Alissa L ; Strachan, Ryan T ; Staus, Dean P ; Wingler, Laura M ; Sun, Lillian D ; Sinnaeve, Justine ; Choi, Minjung ; Cho, Ted ; Xu, Thomas T ; Hansen, Gwenn M ; Burnett, Michael B ; Lamerdin, Jane E ; Bassoni, Daniel L ; Gavino, Bryant J ; Husemoen
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