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Chemoselective small molecules that covalently modify one lysine in a non-enzyme protein in plasma

Academic Article
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Overview

authors

  • Choi, S.
  • Connelly, S.
  • Reixach, Natalia
  • Wilson, Ian
  • Kelly, Jeffery

publication date

  • February 2010

journal

  • Nature Chemical Biology  Journal

abstract

  • A small molecule that could bind selectively to and then react chemoselectively with a non-enzyme protein in a complex biological fluid, such as blood, could have numerous practical applications. Herein, we report a family of designed stilbenes that selectively and covalently modify the prominent plasma protein transthyretin in preference to more than 4,000 other human plasma proteins. They react chemoselectively with only one of eight lysine e-amino groups within transthyretin. The crystal structure confirms the expected binding orientation of the stilbene substructure and the anticipated conjugating amide bond. These covalent transthyretin kinetic stabilizers exhibit superior amyloid inhibition potency compared to their noncovalent counterparts, and they prevent cytotoxicity associated with amyloidogenesis. Though there are a few prodrugs that, upon metabolic activation, react with a cysteine residue inactivating a specific non-enzyme, we are unaware of designed small molecules that react with one lysine e-amine within a specific non-enzyme protein in a complex biological fluid.

subject areas

  • Cell Line, Tumor
  • Cell Survival
  • Crystallography, X-Ray
  • Drug Design
  • Humans
  • Kinetics
  • Lysine
  • Models, Molecular
  • Prealbumin
  • Protein Multimerization
  • Protein Structure, Tertiary
  • Stilbenes
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Identity

PubMed Central ID

  • PMC3107129

International Standard Serial Number (ISSN)

  • 1552-4450

Digital Object Identifier (DOI)

  • 10.1038/nchembio.281

PubMed ID

  • 20081815
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Additional Document Info

start page

  • 133

end page

  • 139

volume

  • 6

issue

  • 2

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