α-Helical Motif as Inhibitors of Toxic Amyloid-β Oligomer Generation via Highly Specific Recognition of Amyloid Surface.

08:00 EDT 18th June 2019 | BioPortfolio

Summary of "α-Helical Motif as Inhibitors of Toxic Amyloid-β Oligomer Generation via Highly Specific Recognition of Amyloid Surface."

Amyloid fibril surfaces can convert soluble proteins into toxic oligomers and are attractive targets for intervention of protein aggregation diseases. Thus far, molecules identified with inhibitory activity are either large proteins or flat cyclic compounds lacking in specificity. The main design difficulty is flatness of amyloid surfaces and the lack of knowledge on binding interfaces. Here, we demonstrate, for the first time, a rational design of alpha-helical peptide inhibitors targeting the amyloid-beta 40 (Aβ40) fibril surfaces, based on our in silico finding that a helical fragment of Aβ40 interacts in a unique way with side-chain arrays on the fibril surface. We strengthen the fragment's binding capability through mutations and helicity enhancement with our Terminal Aspartic acid strategy. The resulting inhibitor shows micromolar affinity for the fibril surface, effectively impedes the surface-mediated oligomerization of Aβ40, and mitigates its cytotoxicity. This work opens up an avenue to designing aggregation modulators for amyloid diseases.


Journal Details

This article was published in the following journal.

Name: iScience
ISSN: 2589-0042
Pages: 87-100


DeepDyve research library

PubMed Articles [15403 Associated PubMed Articles listed on BioPortfolio]

Hsp60 protects against Amyloid β oligomer synaptic toxicity via modification of toxic oligomer conformation.

Alzheimer's disease (AD) is the leading cause of dementia worldwide. While the etiology of AD remains uncertain, neuro-toxic effects of amyloid beta oligomers (Aβo) on synaptic function, a well-estab...

Diverse Structural Conversion and Aggregation Pathways of Alzheimer's Amyloid-β (1-40).

Complex amyloid aggregation of amyloid-β (1-40) (Aβ) in terms of monomer structures has not been fully understood. Herein, we report the microscopic mechanism and pathways of Aβ aggregation with ma...

What is the "Relevant" Amyloid β 42 Concentration?

Alzheimer's Amyloid beta can perform a wide variety of actions that are highly concentration-dependent. This note aims to provide a framework for basic considerations on what might be considered a bra...

Label-free distribution of anti-amyloid D-AIP in Drosophila melanogaster: prevention of Ab42-induced toxicity without side effects in transgenic flies.

Soluble oligomers of the 42-amino acid amyloid-beta (Ab42) peptide are highly toxic and suspected as the causative agent of synaptic dysfunction and neuronal loss in Alzheimer disease (AD). Previously...

Methods for the Construction of Collagen-Based Triple-Helical Peptides Designed as Matrix Metalloproteinase Inhibitors.

The triple-helical structure of collagen has been accurately reproduced in numerous chemical and recombinant model systems. Triple-helical peptides have found application for dissecting collagen-stabi...

Clinical Trials [4157 Associated Clinical Trials listed on BioPortfolio]

Application of Amyloid PET in Cerebral Amyloid Angiopathy

In this project, we will try to enhance the diagnostic potentials of amyloid PET in CAA by combination of dynamic amyloid PET with MRI SWI and MR perfusion images. We will also try to inve...

Helical Tomotherapy as a Radiotherapy Technique for Treating Bone Metastases

To assess the safety and efficacy of a single fraction of radiotherapy using helical tomotherapy to treat bone metastases.

Study to Evaluate the Effect of CT1812 Treatment on Amyloid Beta Oligomer Displacement Into CSF in Subjects With Mild to Moderate Alzheimer's Disease

This is a multi‐center, Phase 1b, randomized, double‐blind, placebo‐controlled parallel‐group trial in adults with mild to moderate AD.

Interleukin-7 and Chemokine (C-C Motif) Ligand 19-expressing CD19-CAR-T for Refractory/Relapsed B Cell Lymphoma.

It's a single arm, open label prospective study, in which the safety and efficacy of Interleukin-7 and Chemokine (C-C Motif) Ligand 19-expressing CD19-CAR-T therapy are evaluated in refrac...

A Healthy Volunteer PK/PD, Safety and Tolerability Study of Second Generation Andexanet Alfa

This is a randomized, double-blind, study in healthy volunteers dosed to steady state with fXa inhibitors, designed to (1) demonstrate PK/PD comparability between andexanet manufactured by...

Medical and Biotech [MESH] Definitions

A type of extracellularly deposited substance composed of an amyloid protein and additional components including HEPARAN SULFATE PROTEOGLYCAN; LAMININ; COLLAGEN TYPE IV; SERUM AMYLOID P-COMPONENT; and APOLIPOPROTEINS E which together form characteristic amyloid fibrils. The core of amyloid fibrils is formed by the stacking of overlapping beta-pleated sheet domains of the amyloid protein. There are many different amyloid proteins that have been found forming the core of the fibrils in vivo. However, amyloid can be formed from any protein that exposes beta-pleated strand conformations during unfolding or refolding. A common characteristic of amyloid is the ability to bind such dyes as CONGO RED and thioflavine.

Proteins that form the core of amyloid fibrils. For example, the core of amyloid A is formed from amyloid A protein, also known as serum amyloid A protein or SAA protein.

A highly toxic compound used as a gasoline additive. It causes acute toxic psychosis or chronic poisoning if inhaled or absorbed through the skin.

Peptides generated from AMYLOID BETA-PEPTIDES PRECURSOR. An amyloid fibrillar form of these peptides is the major component of amyloid plaques found in individuals with Alzheimer's disease and in aged individuals with trisomy 21 (DOWN SYNDROME). The peptide is found predominantly in the nervous system, but there have been reports of its presence in non-neural tissue.

A pancreatic beta-cell hormone that is co-secreted with INSULIN. It displays an anorectic effect on nutrient metabolism by inhibiting gastric acid secretion, gastric emptying and postprandial GLUCAGON secretion. Islet amyloid polypeptide can fold into AMYLOID FIBRILS that have been found as a major constituent of pancreatic AMYLOID DEPOSITS.

Quick Search

DeepDyve research library

Relevant Topic

Alzheimer's Disease
Of all the types of Dementia, Alzheimer's disease is the most common, affecting around 465,000 people in the UK. Neurons in the brain die, becuase  'plaques' and 'tangles' (mis-folded proteins) form in the brain. People with Al...

Searches Linking to this Article