scholarly journals Small molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer’s disease

2019 ◽  
Author(s):  
Gabriella T. Heller ◽  
Francesco A. Aprile ◽  
Thomas C. T. Michaels ◽  
Ryan Limbocker ◽  
Michele Perni ◽  
...  
Keyword(s):  
Small Molecule ◽  
Amyloid Β ◽  
Hydrophobic Surface ◽  
Disordered Proteins ◽  
Amyloid Β Peptide ◽  
Remarkable Effect ◽  
Determination Methods ◽  
Structural Ensemble ◽  
Soluble State

AbstractDisordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that has been shown to modify the properties of their monomeric states. Here, we identify a small molecule capable of binding and sequestering the amyloid-β peptide (Aβ) in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterise this interaction using biophysical experiments and integrative structural ensemble determination methods. We thus observe that this small molecule has the remarkable effect of increasing the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. We then show that this small molecule rescues a Caenorhabditis elegans model of Aβ-associated toxicity in a manner consistent with the mechanism of action identified from the in silico and in vitro studies. These results provide an illustration of the strategy of targeting the monomeric states of disordered proteins with small molecules to alter their behaviour for therapeutic purposes.

scholarly journals Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer’s disease

2020 ◽  
Vol 6 (45) ◽  
pp. eabb5924 ◽  
Author(s):  
Gabriella T. Heller ◽  
Francesco A. Aprile ◽  
Thomas C. T. Michaels ◽  
Ryan Limbocker ◽  
Michele Perni ◽  
...  
Keyword(s):  
Small Molecule ◽  
Amyloid Β ◽  
Hydrophobic Surface ◽  
Disordered Proteins ◽  
Secondary Nucleation ◽  
Intrinsically Disordered ◽  
Determination Methods ◽  
Structural Ensemble ◽  
Soluble State

Disordered proteins are challenging therapeutic targets, and no drug is currently in clinical use that modifies the properties of their monomeric states. Here, we identify a small molecule (10074-G5) capable of binding and sequestering the intrinsically disordered amyloid-β (Aβ) peptide in its monomeric, soluble state. Our analysis reveals that this compound interacts with Aβ and inhibits both the primary and secondary nucleation pathways in its aggregation process. We characterize this interaction using biophysical experiments and integrative structural ensemble determination methods. We observe that this molecule increases the conformational entropy of monomeric Aβ while decreasing its hydrophobic surface area. We also show that it rescues a Caenorhabditis elegans model of Aβ-associated toxicity, consistent with the mechanism of action identified from the in silico and in vitro studies. These results illustrate the strategy of stabilizing the monomeric states of disordered proteins with small molecules to alter their behavior for therapeutic purposes.

scholarly journals A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer’s disease

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Tatsuya Ikenoue ◽  
Francesco A. Aprile ◽  
Pietro Sormanni ◽  
Francesco S. Ruggeri ◽  
Michele Perni ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Rational Design ◽  
Therapeutic Potential ◽  
Amyloid Β ◽  
Disordered Proteins ◽  
Amyloid Β Peptide ◽  
Model Of Alzheimer’S Disease ◽  
Worm Model

Abstract Bicyclic peptides have great therapeutic potential since they can bridge the gap between small molecules and antibodies by combining a low molecular weight of about 2 kDa with an antibody-like binding specificity. Here we apply a recently developed in silico rational design strategy to produce a bicyclic peptide to target the C-terminal region (residues 31–42) of the 42-residue form of the amyloid β peptide (Aβ42), a protein fragment whose aggregation into amyloid plaques is linked with Alzheimer’s disease. We show that this bicyclic peptide is able to remodel the aggregation process of Aβ42 in vitro and to reduce its associated toxicity in vivo in a C. elegans worm model expressing Aβ42. These results provide an initial example of a computational approach to design bicyclic peptides to target specific epitopes on disordered proteins.

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

scholarly journals Repeated electromagnetic field stimulation lowers amyloid-β peptide levels in primary human mixed brain tissue cultures

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Felipe P. Perez ◽  
Bryan Maloney ◽  
Nipun Chopra ◽  
Jorge J. Morisaki ◽  
Debomoy K. Lahiri
Keyword(s):  
Electromagnetic Field ◽  
Late Onset ◽  
Amyloid Β ◽  
Clinical Settings ◽  
Amyloid Β Peptide ◽  
Field Stimulation ◽  
Amino Acid Residues ◽  
Hyperphosphorylated Tau Protein ◽  
Magnetic Resonance Imaging Mri

AbstractLate Onset Alzheimer’s Disease is the most common cause of dementia, characterized by extracellular deposition of plaques primarily of amyloid-β (Aβ) peptide and tangles primarily of hyperphosphorylated tau protein. We present data to suggest a noninvasive strategy to decrease potentially toxic Aβ levels, using repeated electromagnetic field stimulation (REMFS) in primary human brain (PHB) cultures. We examined effects of REMFS on Aβ levels (Aβ40 and Aβ42, that are 40 or 42 amino acid residues in length, respectively) in PHB cultures at different frequencies, powers, and specific absorption rates (SAR). PHB cultures at day in vitro 7 (DIV7) treated with 64 MHz, and 1 hour daily for 14 days (DIV 21) had significantly reduced levels of secreted Aβ40 (p = 001) and Aβ42 (p = 0.029) peptides, compared to untreated cultures. PHB cultures (DIV7) treated at 64 MHz, for 1 or 2 hour during 14 days also produced significantly lower Aβ levels. PHB cultures (DIV28) treated with 64 MHz 1 hour/day during 4 or 8 days produced a similar significant reduction in Aβ40 levels. 0.4 W/kg was the minimum SAR required to produce a biological effect. Exposure did not result in cellular toxicity nor significant changes in secreted Aβ precursor protein-α (sAPPα) levels, suggesting the decrease in Aβ did not likely result from redirection toward the α-secretase pathway. EMF frequency and power used in our work is utilized in human magnetic resonance imaging (MRI, thus suggesting REMFS can be further developed in clinical settings to modulate Aβ deposition.

Effects of Hydrated Forms of C60 Fullerene on Amyloid β-Peptide Fibrillization In Vitro and Performance of the Cognitive Task

2007 ◽  
Vol 7 (4) ◽  
pp. 1479-1485 ◽  
Author(s):  
I. Ya. Podolski ◽  
Z. A. Podlubnaya ◽  
E. A. Kosenko ◽  
E. A. Mugantseva ◽  
E. G. Makarova ◽  
...  
Keyword(s):  
Cognitive Task ◽  
Amyloid Β ◽  
C60 Fullerene ◽  
Amyloid Β Peptide ◽  
And Performance

Gallotannins and Tannic Acid: First Chemical Syntheses and In Vitro Inhibitory Activity on Alzheimer’s Amyloid β-Peptide Aggregation

2015 ◽  
Vol 54 (28) ◽  
pp. 8217-8221 ◽  
Author(s):  
Tahiri Sylla ◽  
Laurent Pouységu ◽  
Grégory Da Costa ◽  
Denis Deffieux ◽  
Jean-Pierre Monti ◽  
...  
Keyword(s):  
Tannic Acid ◽  
Inhibitory Activity ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation
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