Inhibition of alpha-Synuclein Amyloid Fibril Elongation by Blocking Fibril Ends

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F18%3A00490459" target="_blank" >RIV/61388963:_____/18:00490459 - isvavai.cz</a>

Výsledek na webu

<a href="http://dx.doi.org/10.1002/anie.201801071" target="_blank" >http://dx.doi.org/10.1002/anie.201801071</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/anie.201801071" target="_blank" >10.1002/anie.201801071</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Inhibition of alpha-Synuclein Amyloid Fibril Elongation by Blocking Fibril Ends

Popis výsledku v původním jazyce

Misfolding of the protein alpha-synuclein (alpha Syn) into amyloid fibrils plays a central role in the development of Parkinson's disease. Most approaches for the inhibition of alpha Syn fibril formation are based on stabilizing the native monomeric form of the protein or destabilizing the fibrillized misfolded form. They require high concentrations of inhibitor and therefore cannot be easily used for therapies. In this work, we designed an inhibitor (Inh-beta) that selectively binds the growing ends of alpha Syn fibrils and creates steric hindrance for the binding of monomeric alpha Syn. This approach permits the inhibition of fibril formation at Inh-beta concentrations (IC50=850nm) much lower than the concentration of monomeric alpha Syn. We studied its kinetic mechanism invitro and identified the reactions that limit inhibition efficiency. It is shown that blocking of alpha Syn fibril ends is an effective approach to inhibiting fibril growth and provides insights for the development of effective inhibitors of alpha Syn aggregation.

Název v anglickém jazyce

Inhibition of alpha-Synuclein Amyloid Fibril Elongation by Blocking Fibril Ends

Popis výsledku anglicky

Misfolding of the protein alpha-synuclein (alpha Syn) into amyloid fibrils plays a central role in the development of Parkinson's disease. Most approaches for the inhibition of alpha Syn fibril formation are based on stabilizing the native monomeric form of the protein or destabilizing the fibrillized misfolded form. They require high concentrations of inhibitor and therefore cannot be easily used for therapies. In this work, we designed an inhibitor (Inh-beta) that selectively binds the growing ends of alpha Syn fibrils and creates steric hindrance for the binding of monomeric alpha Syn. This approach permits the inhibition of fibril formation at Inh-beta concentrations (IC50=850nm) much lower than the concentration of monomeric alpha Syn. We studied its kinetic mechanism invitro and identified the reactions that limit inhibition efficiency. It is shown that blocking of alpha Syn fibril ends is an effective approach to inhibiting fibril growth and provides insights for the development of effective inhibitors of alpha Syn aggregation.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10610 - Biophysics

Projekt

<a href="/cs/project/GJ18-06255Y" target="_blank" >GJ18-06255Y: Nová strategie pro inhibici tvorby amyloidních fibril</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2018

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Angewandte Chemie - International Edition

ISSN

1433-7851

e-ISSN

—

Svazek periodika

57

Číslo periodika v rámci svazku

20

Stát vydavatele periodika

DE - Spolková republika Německo

Počet stran výsledku

5

Strana od-do

5690-5694

Kód UT WoS článku

000431488200017

EID výsledku v databázi Scopus

2-s2.0-85045376750