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Click-generated triazole ureas as ultrapotent in vivo-active serine hydrolase inhibitors

Academic Article
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Overview

related to degree

  • Bachovchin, Daniel A., Ph.D. in Chemistry, Scripps Research 2006 - 2011

authors

  • Adibekian, Alexander
  • Martin, B. R.
  • Wang, C.
  • Hsu, K. L.
  • Bachovchin, Daniel A.
  • Niessen, Sherry
  • Hoover, H.
  • Cravatt, Benjamin

publication date

  • July 2011

journal

  • Nature Chemical Biology  Journal

abstract

  • Serine hydrolases are a diverse enzyme class representing ?1% of all human proteins. The biological functions of most serine hydrolases remain poorly characterized owing to a lack of selective inhibitors to probe their activity in living systems. Here we show that a substantial number of serine hydrolases can be irreversibly inactivated by 1,2,3-triazole ureas, which show negligible cross-reactivity with other protein classes. Rapid lead optimization by click chemistry-enabled synthesis and competitive activity-based profiling identified 1,2,3-triazole ureas that selectively inhibit enzymes from diverse branches of the serine hydrolase class, including peptidases (acyl-peptide hydrolase, or APEH), lipases (platelet-activating factor acetylhydrolase-2, or PAFAH2) and uncharacterized hydrolases (?,?-hydrolase-11, or ABHD11), with exceptional potency in cells (sub-nanomolar) and mice (<1 mg kg(-1)). We show that APEH inhibition leads to accumulation of N-acetylated proteins and promotes proliferation in T cells. These data indicate 1,2,3-triazole ureas are a pharmacologically privileged chemotype for serine hydrolase inhibition, combining broad activity across the serine hydrolase class with tunable selectivity for individual enzymes.
  • Serine hydrolases are a diverse enzyme class representing ∼1% of all human proteins. The biological functions of most serine hydrolases remain poorly characterized owing to a lack of selective inhibitors to probe their activity in living systems. Here we show that a substantial number of serine hydrolases can be irreversibly inactivated by 1,2,3-triazole ureas, which show negligible cross-reactivity with other protein classes. Rapid lead optimization by click chemistry-enabled synthesis and competitive activity-based profiling identified 1,2,3-triazole ureas that selectively inhibit enzymes from diverse branches of the serine hydrolase class, including peptidases (acyl-peptide hydrolase, or APEH), lipases (platelet-activating factor acetylhydrolase-2, or PAFAH2) and uncharacterized hydrolases (α,β-hydrolase-11, or ABHD11), with exceptional potency in cells (sub-nanomolar) and mice (<1 mg kg(-1)). We show that APEH inhibition leads to accumulation of N-acetylated proteins and promotes proliferation in T cells. These data indicate 1,2,3-triazole ureas are a pharmacologically privileged chemotype for serine hydrolase inhibition, combining broad activity across the serine hydrolase class with tunable selectivity for individual enzymes.

subject areas

  • Animals
  • Brain
  • Cell Line, Tumor
  • Click Chemistry
  • Humans
  • Mice
  • Molecular Structure
  • Myocardium
  • Serine Proteases
  • Serine Proteinase Inhibitors
  • T-Lymphocytes
  • Transfection
  • Triazoles
  • Urea
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Identity

PubMed Central ID

  • PMC3118922

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.579

PubMed ID

  • 21572424
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Additional Document Info

start page

  • 469

end page

  • 478

volume

  • 7

issue

  • 7

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