Development of curcumin-based amyloid β aggregation inhibitors for Alzheimer's disease using the SAR matrix approach

2021 ◽  
pp. 116357
Author(s):  
Rohmad Yudi Utomo ◽  
Yasunobu Asawa ◽  
Satoshi Okada ◽  
Hyun Seung Ban ◽  
Atsushi Yoshimori ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Matrix Approach ◽  
Aggregation Inhibitors

scholarly journals Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer's disease brain tissue

2021 ◽  
Vol 118 (4) ◽  
pp. e2023089118 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Kent R. Thurber ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Molecular Conformations ◽  
Layered Architecture ◽  
Fibril Structure ◽  
Aggregation Inhibitors ◽  
Aβ Fibrils ◽  
Β Sheet

Amyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may contribute to variations in clinical and pathological characteristics of Alzheimer’s disease (AD). We report the molecular structure of a specific fibril polymorph, formed by 40-residue Aβ peptides (Aβ40), that is derived from cortical tissue of an AD patient by seeded fibril growth. The structure is determined from cryogenic electron microscopy (cryoEM) images, supplemented by mass-per-length (MPL) measurements and solid-state NMR (ssNMR) data. Previous ssNMR studies with multiple AD patients had identified this polymorph as the most prevalent brain-derived Aβ40 fibril polymorph from typical AD patients. The structure, which has 2.8-Å resolution according to standard criteria, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformations and its organization of cross-β subunits. Unique features include twofold screw symmetry about the fibril growth axis, despite an MPL value that indicates three Aβ40 molecules per 4.8-Å β-sheet spacing, a four-layered architecture, and fully extended conformations for molecules in the central two cross-β layers. The cryoEM density, ssNMR data, and MPL data are consistent with β-hairpin conformations for molecules in the outer cross-β layers. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

Recent advances in the design and applications of amyloid-β peptide aggregation inhibitors for Alzheimer’s disease therapy

2019 ◽  
Vol 11 (6) ◽  
pp. 901-925 ◽  
Author(s):  
Safura Jokar ◽  
Saeedeh Khazaei ◽  
Hossein Behnammanesh ◽  
Amir Shamloo ◽  
Mostafa Erfani ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Peptide Aggregation ◽  
Recent Advances ◽  
Disease Therapy ◽  
Aggregation Inhibitors

scholarly journals Small-Molecule Amyloid Beta-Aggregation Inhibitors in Alzheimer's Disease Drug Development

2019 ◽  
Vol 01 (01) ◽  
pp. e22-e32
Author(s):  
Sharmin Reza Chowdhury ◽  
Fangzhou Xie ◽  
Jinxin Gu ◽  
Lei Fu
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Small Molecule ◽  
Disease Process ◽  
Amyloid Β ◽  
Symptomatic Improvement ◽  
Starting Point ◽  
Aβ Aggregation ◽  
Aggregation Inhibitors

AbstractAlzheimer's disease (AD) is still an incurable neurodegenerative disease that causes dementia. AD changes the brain function that, over time, impairs memory and diminishes judgment and reasoning ability. Pathophysiology of AD is complex. Till now the cause of AD remains unknown, but risk factors include family history and genetic predisposition. The drugs previously approved for AD treatment do not modify the disease process and only provide symptomatic improvement. Over the past few decades, research has led to significant progress in the understanding of the disease, leading to several novel strategies that may modify the disease process. One of the major developments in this direction is the amyloid β (Aβ) aggregation. Small molecules could block the initial stages of Aβ aggregation, which could be the starting point for the design and development of new AD drugs in the near future. In this review we summarize the most promising small-molecule Aβ-aggregation inhibitors including natural compounds, novel small molecules, and also those are in clinical trials. Moreover, we briefly summarized some reported docking studies of small-molecule Aβ aggregation inhibitors. These will give us an idea about the chemical features required to design novel small molecules with anti-Aβ aggregation properties.

scholarly journals d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2387 ◽  
Author(s):  
Banafsheh Mehrazma ◽  
Stanley Opare ◽  
Anahit Petoyan ◽  
Arvi Rauk
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Dynamics ◽  
Amino Acid ◽  
Amyloid Β ◽  
Md Simulations ◽  
Causative Factor ◽  
Umbrella Sampling ◽  
Aggregation Inhibitors ◽  
Dynamics Simulations

A causative factor for neurotoxicity associated with Alzheimer’s disease is the aggregation of the amyloid-β (Aβ) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out to study the interaction of the pseudo-peptides with both Aβ13–23 (the core recognition site of Aβ) and full-length Aβ1–42. Umbrella sampling MD calculations have been used to estimate the free energy of binding, ∆G, of these peptides to Aβ13–23. The highest ∆Gbinding is found for SGB1. Each of the pseudo-peptides was also docked to Aβ1–42 and subjected up to seven microseconds of all atom molecular dynamics simulations. The resulting structures lend insight into how the dynamics of Aβ1–42 are altered by complexation with the pseudo-peptides and confirmed that SGB1 may be a better candidate for developing into a drug to prevent Alzheimer’s disease.

Protein-Protein Interactions and Aggregation Inhibitors in Alzheimer’s Disease

2019 ◽  
Vol 19 (7) ◽  
pp. 501-533 ◽  
Author(s):  
Ankit Ganeshpurkar ◽  
Rayala Swetha ◽  
Devendra Kumar ◽  
Gore P. Gangaram ◽  
Ravi Singh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Interactions ◽  
Critical Role ◽  
Pdz Domain ◽  
Amyloid Β ◽  
Cellular Prion Protein ◽  
Protein Protein Interactions ◽  
Phosphatase 2A ◽  
Aggregation Inhibitors

Background:Alzheimer’s Disease (AD), a multifaceted disorder, involves complex pathophysiology and plethora of protein-protein interactions. Thus such interactions can be exploited to develop anti-AD drugs.Objective:The interaction of dynamin-related protein 1, cellular prion protein, phosphoprotein phosphatase 2A and Mint 2 with amyloid β, etc., studied recently, may have critical role in progression of the disease. Our objective has been to review such studies and their implications in design and development of drugs against the Alzheimer’s disease.Methods:Such studies have been reviewed and critically assessed.Results:Review has led to show how such studies are useful to develop anti-AD drugs.Conclusion:There are several PPIs which are current topics of research including Drp1, Aβ interactions with various targets including PrPC, Fyn kinase, NMDAR and mGluR5 and interaction of Mint2 with PDZ domain, etc., and thus have potential role in neurodegeneration and AD. Finally, the multi-targeted approach in AD may be fruitful and opens a new vista for identification and targeting of PPIs in various cellular pathways to find a cure for the disease.

scholarly journals Molecular structure of a prevalent amyloid-β fibril polymorph from Alzheimer’s disease brain tissue

2020 ◽  
Author(s):  
Ujjayini Ghosh ◽  
Kent R. Thurber ◽  
Wai-Ming Yau ◽  
Robert Tycko
Keyword(s):  
Molecular Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Molecular Conformation ◽  
Amyloid Β ◽  
Cryo Electron Microscopy ◽  
Nmr Data ◽  
Fibril Structure ◽  
Aggregation Inhibitors ◽  
Aβ Fibrils

AbstractAmyloid-β (Aβ) fibrils exhibit self-propagating, molecular-level polymorphisms that may underlie variations in clinical and pathological characteristics of Alzheimer’s disease. We report the molecular structure of a specific brain-derived polymorph that has been identified as the most prevalent polymorph of 40-residue Aβ fibrils in cortical tissue of Alzheimer’s disease patients. This structure, developed from cryo-electron microscopy and supported by solid state NMR data, differs qualitatively from all previously described Aβ fibril structures, both in its molecular conformation and its organization of cross-β subunits. Knowledge of this brain-derived fibril structure may contribute to the development of structure-specific amyloid imaging agents and aggregation inhibitors with greater diagnostic and therapeutic utility.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
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.

Minimalistic Design Approach for Multi-Reactivity against Free Radicals and Metal-Free and Metal-Bound Amyloid-β Peptides: Redox-Based Substitutions of Benzene

2019 ◽  
Author(s):  
Mingeun Kim ◽  
Juhye Kang ◽  
Misun Lee ◽  
Jiyeon Han ◽  
Geewoo Nam ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Free Radicals ◽  
Amyloid Β ◽  
Design Strategy ◽  
Design Approach ◽  
Metal Free

We report a minimalistic redox-based design strategy for engineering compact molecules based on the simplest aromatic framework, benzene, with multi-reactivity against free radicals, metal-free amyloid-β, and metal-bound amyloid-β, implicated in the most common form of dementia, Alzheimer’s disease.

Neuroinflammation and Complexes of 17β -Hydroxysteroid Dehydrogenase type 10 - Amyloid β in Alzheimer's Disease

2013 ◽  
Vol 10 (2) ◽  
pp. 165-173 ◽  
Author(s):  
Zdena Kristofikova ◽  
Daniela Ripova ◽  
Ales Bartos ◽  
Marketa Bockova ◽  
Katerina Hegnerova ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
Hydroxysteroid Dehydrogenase
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