Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

Abstract

Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no diseasemodifying 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.

Molecular tweezers for lysine and arginine – powerful inhibitors of pathologic protein aggregation

“…Other modulators of Aβ assembly have been shown to bind only at oligomeric/aggregated 0states. 79, 80 In model experiments with Aβ15–29, specific inclusion of Lys side chains was detected directly by large upfield shifts of up to 4 ppm matching the earlier results with small Lys derivatives.…”

Transthyretin Mimetics as Anti‐β‐Amyloid Agents: A Comparison of Peptide and Protein Approaches

“…[23f, 24] For example, EGCG inhibits fibrillogenesis not only for Aβ, but also for amylin, α-synuclein, huntingtin, and prion. [25] Antibodies such as A11 show broad cross-reactivity with oligomeric amyloid-related intermediates. [23f, 24] While having a therapeutic capable of targeting multiple amyloidogenic proteins has its benefits, it also brings into question the specificity of these compounds.…”

Targeting protein aggregation for the treatment of degenerative diseases

“…EGCG (Table 1) is able to remodel protein aggregates, including amyloid fibrils and oligomers, comprising different amyloidogenic proteins, although the mechanistic underpinnings of this process are not entirely clear 191-198 . Ample evidence shows that the EGCG amyloid remodeling activity in vitro is dependent on auto-oxidation of the EGCG molecule.…”