Inhibition of protein misfolding and aggregation by natural phenolic compounds

Cell Mol Life Sci. 2018 Oct;75(19):3521-3538. doi: 10.1007/s00018-018-2872-2. Epub 2018 Jul 20.


Protein misfolding and aggregation into fibrillar deposits is a common feature of a large group of degenerative diseases affecting the central nervous system or peripheral organs, termed protein misfolding disorders (PMDs). Despite their established toxic nature, clinical trials aiming to reduce misfolded aggregates have been unsuccessful in treating or curing PMDs. An interesting possibility for disease intervention is the regular intake of natural food or herbal extracts, which contain active molecules that inhibit aggregation or induce the disassembly of misfolded aggregates. Among natural compounds, phenolic molecules are of particular interest, since most have dual activity as amyloid aggregation inhibitors and antioxidants. In this article, we review many phenolic natural compounds which have been reported in diverse model systems to have the potential to delay or prevent the development of various PMDs, including Alzheimer's and Parkinson's diseases, prion diseases, amyotrophic lateral sclerosis, systemic amyloidosis, and type 2 diabetes. The lower toxicity of natural compounds compared to synthetic chemical molecules suggest that they could serve as a good starting point to discover protein misfolding inhibitors that might be useful for the treatment of various incurable diseases.

Keywords: Aggregates; Alpha-synuclein; Alzheimer’s disease; Amylin; Amyloid beta; Amyloid inhibitors; Flavonoids; Misfolded proteins; Natural compounds; Parkinson’s disease; Polyphenols; Prion diseases; Protein misfolding disorders; Tau; Type 2 diabetes.

Publication types

  • Review

MeSH terms

  • Amyloidosis / drug therapy
  • Amyloidosis / metabolism
  • Amyloidosis / pathology
  • Animals
  • Biological Products / pharmacology*
  • Biological Products / therapeutic use
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • Humans
  • Phenols / pharmacology*
  • Phenols / therapeutic use
  • Prion Diseases / drug therapy
  • Prion Diseases / metabolism
  • Prion Diseases / pathology
  • Protein Aggregation, Pathological / prevention & control*
  • Protein Folding / drug effects*
  • Proteostasis Deficiencies / drug therapy
  • Proteostasis Deficiencies / prevention & control*


  • Biological Products
  • Phenols