A Ratiometric Fluorescent Conjugated Oligomer for Amyloid β Recognition, Aggregation Inhibition, and Detoxification

: Alzheimer's Disease (AD) is a neurodegenerative disorder with an increasing impact on society. Because currently available therapy has only a short-term effect, a huge number of novel compounds are developed every year exploiting knowledge of the various aspects of AD pathophysiology. To better address the pathological complexity of AD, one of the most extensively pursued strategies by medicinal chemists is based on Multi-target-directed Ligands (MTDLs). Donepezil is one of the currently approved drugs for AD therapy acting as an acetylcholinesterase inhibitor. In this review, we have made an extensive literature survey focusing on donepezil-derived MTDL hybrids primarily targeting on different levels cholinesterases and amyloid beta (Aβ) peptide. The targeting includes direct interaction of the compounds with Aβ, AChE-induced Aβ aggregation, inhibition of BACE-1 enzyme, and modulation of biometal balance thus impeding Aβ assembly.

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Novel Donepezil–Arylsulfonamide Hybrids as Multitarget-Directed Ligands for Potential Treatment of Alzheimer’s Disease

Molecules ◽

10.3390/molecules26061658 ◽

2021 ◽

Vol 26 (6) ◽

pp. 1658

Author(s):

Fausto Queda ◽

Sonia Calò ◽

Karolina Gwizdala ◽

João D. Magalhães ◽

Sandra M. Cardoso ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Ache Inhibitor ◽

Target Drug ◽

Aβ Aggregation ◽

Aggregation Inhibition ◽

Inhibitor Drug ◽

A Current

Alzheimer’s disease (AD) is one of the most devastating neurodegenerative disorders, characterized by multiple pathological features. Therefore, multi-target drug discovery has been one of the most active fields searching for new effective anti-AD therapies. Herein, a series of hybrid compounds are reported which were designed and developed by combining an aryl-sulfonamide function with a benzyl-piperidine moiety, the pharmacophore of donepezil (a current anti-AD acetylcholinesterase AChE inhibitor drug) or its benzyl-piperazine analogue. The in vitro results indicate that some of these hybrids achieve optimized activity towards two main AD targets, by displaying excellent AChE inhibitory potencies, as well as the capability to prevent amyloid-β (Aβ) aggregation. Some of these hybrids also prevented Aβ-induced cell toxicity. Significantly, drug-like properties were predicted, including for blood-brain permeability. Compound 9 emerged as a promising multi-target lead compound (AChE inhibition (IC50 1.6 μM); Aβ aggregation inhibition 60.7%). Overall, this family of hybrids is worthy of further exploration, due to the wide biological activity of sulfonamides.

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Photodynamic micelles for amyloid β degradation and aggregation inhibition

Chemical Communications ◽

10.1039/c6cc06175c ◽

2016 ◽

Vol 52 (81) ◽

pp. 12044-12047 ◽

Cited By ~ 11

Author(s):

Junying Zhang ◽

Jianping Liu ◽

Yingying Zhu ◽

Zhiai Xu ◽

Jie Xu ◽

...

Keyword(s):

Polymeric Micelles ◽

Amyloid Β ◽

Tanshinone I ◽

Aggregation Inhibition

Tanshinone I-loaded photodynamic polymeric micelles were reported for photodegrading amyloid β (Aβ) aggregates and inhibiting Aβ fibrillation.

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Identification of [PtCl2(phen)] Binding Modes in Amyloid-β Peptide and the Mechanism of Aggregation Inhibition

Chemistry - A European Journal ◽

10.1002/chem.201101859 ◽

2011 ◽

Vol 17 (41) ◽

pp. 11657-11666 ◽

Cited By ~ 55

Author(s):

Guolin Ma ◽

Fan Huang ◽

Xuewei Pu ◽

Liangyuan Jia ◽

Tao Jiang ◽

...

Keyword(s):

Amyloid Β ◽

Amyloid Β Peptide ◽

Binding Modes ◽

Aggregation Inhibition

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Simulations on the dual effects of flavonoids as suppressors of Aβ42 fibrillogenesis and destabilizers of mature fibrils

Scientific Reports ◽

10.1038/s41598-020-72734-9 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Sahar Andarzi Gargari ◽

Abolfazl Barzegar

Keyword(s):

Amyloid Β ◽

Atomic Scale ◽

Amyloid Β Peptide ◽

Salt Bridges ◽

Linear Interaction ◽

Computational Evaluation ◽

High Interaction ◽

Aβ Aggregation ◽

Aggregation Inhibition ◽

Β Sheets

Abstract Structural studies of the aggregation inhibition of the amyloid-β peptide (Aβ) by different natural compounds are of the utmost importance due to their great potential as neuroprotective and therapeutic agents for Alzheimer’s disease. We provided the simulation of molecular dynamics for two different states of Aβ42, including “monomeric aggregation-prone state (APS)” and “U-shaped pentamers of amyloidogenic protofilament intermediates” in the absence and presence of polyphenolic flavonoids (Flvs, myricetin and morin) in order to verify the possible mechanism of Flvs fibrillogenesis suppression. Data showed that Flvs directly bind into Aβ42 species in both states of “monomeric APS β-sheets” and “pentameric amyloidogenic intermediates”. Binding of Flvs with amyloidogenic protofilament intermediates caused the attenuation of some inter-chains H-bonds, salt bridges, van der Waals and interpeptide interaction energies without interfering with their secondary β-sheets. Therefore, Flvs redirect oligomeric amyloidogenic intermediates into unstructured aggregates by significant disruption of the "steric zipper" motif of fibrils—pairs of self-complementary β-sheets—without changing the amount of β-sheets. It is while Flvs completely destruct the disadvantageous secondary β-sheets of monomeric APS conformers by converting them into coil/helix structures. It means that Flvs suppress the fibrillogenesis process of the monomeric APS structures by converting their β-sheets into proper soluble coil/helices structures. The different actions of Flvs in contact with two different states of Aβ conformers are related to high interaction tendency of Flvs with additional H-bonds for monomeric APS β-sheet, rather than oligomeric protofilaments. Linear interaction energy (LIE) analysis confirmed the strong binding of monomeric Aβ-Flvs with more negative ∆Gbinding, rather than oligomeric Aβ-Flvs system. Therefore, atomic scale computational evaluation of Flvs actions demonstrated different dual functions of Flvs, concluded from the application of two different monomeric and pentameric Aβ42 systems. The distinct dual functions of Flvs are proposed as suppressing the aggregation by converting β-sheets of monomeric APS to proper soluble structures and disrupting the "steric zipper" fibril motifs of oligomeric intermediate by converting on-pathway into off-pathway. Taken together, our data propose that Flvs exert dual and more effective functions against monomeric APS (fibrillogenesis suppression) and remodel the Aβ aggregation pathway (fibril destabilization).

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Evaluation of Amyloid Polypeptide Aggregation Inhibition and Disaggregation Activity of A-Type Procyanidins

Pharmaceuticals ◽

10.3390/ph14111118 ◽

2021 ◽

Vol 14 (11) ◽

pp. 1118

Author(s):

Taisei Tanaka ◽

Vipul V. Betkekar ◽

Ken Ohmori ◽

Keisuke Suzuki ◽

Hideyuki Shigemori

Keyword(s):

Daily Intake ◽

Amyloid Β ◽

Islet Amyloid ◽

Transmission Electron ◽

Amyloid Aggregates ◽

Aggregation Inhibition ◽

Aggregation And Disaggregation ◽

Amyloid Polypeptides ◽

The Brain

The number of people worldwide suffering from Alzheimer’s disease (AD) and type 2 diabetes (T2D) is on the rise. Amyloid polypeptides are thought to be associated with the onset of both diseases. Amyloid-β (Aβ) that aggregates in the brain and human islet amyloid polypeptide (hIAPP) that aggregates in the pancreas are considered cytotoxic and the cause of the development of AD and T2D, respectively. Thus, inhibiting amyloid polypeptide aggregation and disaggregation existing amyloid aggregates are promising approaches in the therapy and prevention against both diseases. Therefore, in this research, we evaluated the Aβ/hIAPP anti-aggregation and disaggregation activities of A-type procyanidins 1–7 and their substructures 8 and 9, by conducting structure–activity relationship studies and identified the active site. The thioflavin-T (Th-T) assay, which quantifies the degree of aggregation of amyloid polypeptides based on fluorescence intensity, and transmission electron microscopy (TEM), employed to directly observe amyloid polypeptides, were used to evaluate the activity. The results showed that catechol-containing compounds 1–6 exhibited Aβ/hIAPP anti-aggregation and disaggregation activities, while compound 7, without catechol, showed no activity. This suggests that the presence of catechol is important for both activities. Daily intake of foods containing A-type procyanidins may be effective in the prevention and treatment of both diseases.

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Amyloid β-peptide and Alzheimer's disease

Essays in Biochemistry ◽

10.1042/bse0560099 ◽

2014 ◽

Vol 56 ◽

pp. 99-110 ◽

Cited By ~ 15

Author(s):

David Allsop ◽

Jennifer Mayes

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Senile Plaques ◽

Strong Support ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Amyloid Cascade Hypothesis ◽

Sequence Of Events ◽

Aβ Amyloid ◽

Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

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