The development of highly potent and selective small molecule correctors of Z α1-antitrypsin misfolding

Bioorg Med Chem Lett. 2021 Jun 1;41:127973. doi: 10.1016/j.bmcl.2021.127973. Epub 2021 Mar 19.

Abstract

α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.

Keywords: 2-Oxindole; Misfolding; α1-Antitrypsin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallization
  • Drug Design*
  • Drug Development / methods
  • Drug Evaluation, Preclinical
  • Endoplasmic Reticulum / metabolism
  • Gene Library
  • Hepatocytes / metabolism
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Protein Folding*
  • alpha 1-Antitrypsin / genetics
  • alpha 1-Antitrypsin / metabolism*

Substances

  • alpha 1-Antitrypsin