Modulating Self‐Assembly of Amyloidogenic Proteins as a Therapeutic Approach for Neurodegenerative Diseases: Strategies and Mechanisms

Abstract

Abnormal protein assembly causes multiple devastating disorders in the central nervous system (CNS), such as Alzheimer's, Parkinson's, Huntington's, and prion diseases. Due to the now extended human lifespan, these diseases have been increasing in prevalence, resulting in major public health problems and the associated financial difficulties worldwide. The wayward proteins that lead to disease self-associate into neurotoxic oligomers and go on to form fibrillar polymers through multiple pathways. Thus, a range of possible targets for pharmacotherapeutic intervention exists along these pathways. Many compounds have shown different levels of effectiveness in inhibiting aberrant self-assembly, dissociating existing aggregates, protecting cells against neurotoxic insults, and in some cases ameliorating disease symptoms in vivo, yet achieving efficient, disease-modifying therapy in humans remains a major unattained goal. To a large degree, this is because the mechanisms of action for these drugs are essentially unknown. For successful design of new effective drugs, it is crucial to elucidate the mechanistic details of their action, including the actual target(s) along the protein aggregation pathways, how the compounds modulate these pathways, and their effect at the cellular, tissue, organ, and organism level. Here, the current knowledge of major mechanisms by which some of the more extensively explored drug candidates work are discussed. In particular, we focus on three prominent strategies: 1) stabilizing the native fold of amyloidogenic proteins, 2) accelerating the aggregation pathways towards the fibrillar endpoint thereby reducing accumulation of toxic oligomers, and 3) modulating the assembly process towards nontoxic oligomers/aggregates. The merit of each strategy is assessed, and the key points to consider when analyzing the efficacy of possible drug candidates and their mechanism of action are discussed.

Comparison of Three Amyloid Assembly Inhibitors: The Sugar scyllo-Inositol, the Polyphenol Epigallocatechin Gallate, and the Molecular Tweezer CLR01

“…Each of the three compounds is believed to modulate the assembly of Aβ into formation of nontoxic structures. 40 Our data suggest that the concentration of scyllo-inositol required for this modulation is substantially higher than those of CLR01 and EGCG. Thus, consistent with the oligomerization and aggregation data, cell death experiments using three different types of cell cultures showed significant inhibition of Aβ42-induced toxicity by CLR01 and EGCG but only mild effects of scyllo-inositol under the same conditions (Figure 4).…”

Modulators of amyloid protein aggregation and toxicity: EGCG and CLR01

“…As Lys is the only proteinogenic amino acid that effectively forms both hydrophobic and electrostatic interactions in peptides and proteins and contributes substantially to these early self-assembly processes, the ability of MTs to bind specifically to the amino acid Lys was hypothesized to interfere with both these types of interactions within and among polypeptides [9,65]. This hypothesis was tested and concluded to be true by our group and our many collaborators over the last several years.…”

“…With the realization that oligomers, rather than fibrils, likely were the primary culprits, the focus shifted towards reducing the steady-state concentration of the toxic oligomers [7][8][9]. However, the therapeutic applicability of this approach is questionable because amyloid deposits may be toxic themselves, the very process of their growth may contribute to cytotoxicity and tissue damage [10], and accelerating fibril formation may induce a harmful pro-inflammatory response [11].…”

“…The mode of action of these compounds, i.e., how they interact with amyloidogenic proteins or why the polyphenolic/flavonoid structures confer affinity for amyloid sequences, is unclear. Nevertheless, it has become evident that the binding of these compounds to the red-wine component resveratrol [27], or the coffee-bean extracted caffeic acid [28,29] can modulate the self-assembly process and inhibit the toxicity of multiple proteins [9]. Many of these compounds have additional activities, including anti-oxidant, anti-inflammatory, or chelatory actions that often are considered beneficial for treatment of amyloid-related Here, we compare EGCG with a drug candidate developed in our laboratory, the molecular tweezer CLR01, which in contrast to EGCG and the other small molecules mentioned above, was tested for its ability to inhibit protein self-assembly and toxicity based on a mechanistic rationale [65].…”

Efeito Protetor Do Resveratrol Na Doença De Alzheimer

“…O resveratrol pode realmente interferir na cascata amiloide através de suas propriedades antinflamatórias e antioxidantes reduzindo assim a produção de espécies reativas de oxigênio, bem como diminuindo a neuroinflamação (LIU, BITAN, 2012). Embora os efeitos sobre a hiperfosforilação de tau serem pouco investigados, a ativação da sirtuína (SIRT1) pelo resveratrol pode conduzir a uma desacetilação direta de tau, promovendo assim a sua degradação proteolítica (MIN et al, 2010).…”