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Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

  • Review Article
  • Published:
Translational Neuroscience

Abstract

Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no disease-modifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies — the green-tea derivative (−)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01’s effects on amyloid β-protein, α-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.

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Abbreviations

ADAD:

Alzheimer’s disease

AFM:

Atomic force microscopy

Aβ:

Amyloid beta

APP:

Amyloid β-protein precursor

COMT:

Catechol-O-methyltransferase

CYP 450:

Cytochrome P450

EC:

Epicatechin

ECG:

Epicatechin-3-gallate

EGC:

Epigallocatechin

EGCG:

Epigallocatechin-3-gallate

EM:

Electron microscopy

FAP:

Familial amyloidotic polyneuropathy

IAPP:

Islet amyloid polypeptide

IC50:

Half maximal inhibitory concentration

IP:

Intraperitoneal

MPTP:

1 - Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

MT:

Molecular tweezer

MTT:

3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide

NBT:

Nitroblue-tetrazolium

NMR:

Nuclear magnetic resonance

PD:

Parkinson’s disease

SDS-PAGE:

Sodium dodecyl sulfate polyacrylamide gel electrophoresis

SPRi:

Surface plasmon resonance imaging

ThT:

Thioflavin T

TTR:

Transthyretin

UPS:

Ubiquitin-proteasome system

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Authors and Affiliations

  1. Department of Neurology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, 90025, USA

    Aida Attar & Gal Bitan

  2. Brain Research Institute, University of California at Los Angeles, Los Angeles, CA, 90025, USA

    Aida Attar & Gal Bitan

  3. Molecular Biology Institute, University of California at Los Angeles, Los Angeles, CA, 90025, USA

    Gal Bitan

  4. Research School of Biology, College of Medicine, Biology, and Environment, The Australian National University, Canberra, ACT, 0200, Australia

    Farid Rahimi

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  1. Aida Attar
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  2. Farid Rahimi
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  3. Gal Bitan
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Correspondence to Gal Bitan.

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Attar, A., Rahimi, F. & Bitan, G. Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01. Translat.Neurosci. 4, 385–409 (2013). https://doi.org/10.2478/s13380-013-0137-y

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