Small molecules that target protein misfolding

J Med Chem. 2012 Dec 27;55(24):10823-43. doi: 10.1021/jm301182j. Epub 2012 Nov 1.

Abstract

Protein misfolding is a process in which proteins are unable to attain or maintain their biologically active conformation. Factors contributing to protein misfolding include missense mutations and intracellular factors such as pH changes, oxidative stress, or metal ions. Protein misfolding is linked to a large number of diseases such as cystic fibrosis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and less familiar diseases such as Gaucher's disease, nephrogenic diabetes insipidus, and Creutzfeldt-Jakob disease. In this Perspective, we report on small molecules that bind to and stabilize the aberrant protein, thereby helping it to attain a native or near-native conformation and restoring its function. The following targets will be specifically discussed: transthyretin, p53, superoxide dismutase 1, lysozyme, serum amyloid A, prions, vasopressin receptor 2, and α-1-antitrypsin.

MeSH terms

  • Amyloid / metabolism
  • Animals
  • Humans
  • Models, Molecular
  • Muramidase / chemistry
  • Muramidase / physiology
  • Mutation
  • Neurodegenerative Diseases / drug therapy*
  • Neurodegenerative Diseases / metabolism
  • Prealbumin / chemistry
  • Prealbumin / physiology
  • Prions / chemistry
  • Prions / physiology
  • Protein Binding
  • Protein Conformation
  • Protein Folding*
  • Proteins / chemistry*
  • Proteins / physiology*
  • Proteostasis Deficiencies / drug therapy*
  • Proteostasis Deficiencies / metabolism
  • Receptors, Vasopressin / chemistry
  • Receptors, Vasopressin / physiology
  • Serum Amyloid A Protein / chemistry
  • Serum Amyloid A Protein / physiology
  • Small Molecule Libraries / chemistry*
  • Small Molecule Libraries / pharmacology
  • Superoxide Dismutase / chemistry
  • Superoxide Dismutase / physiology
  • Superoxide Dismutase-1
  • Tumor Suppressor Protein p53 / chemistry
  • Tumor Suppressor Protein p53 / physiology
  • Unfolded Protein Response
  • alpha 1-Antitrypsin / chemistry
  • alpha 1-Antitrypsin / physiology

Substances

  • Amyloid
  • Prealbumin
  • Prions
  • Proteins
  • Receptors, Vasopressin
  • SOD1 protein, human
  • Serum Amyloid A Protein
  • Small Molecule Libraries
  • Tumor Suppressor Protein p53
  • alpha 1-Antitrypsin
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • Muramidase