Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F21%3A00543021" target="_blank" >RIV/61388963:_____/21:00543021 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11310/21:10430068

Výsledek na webu

<a href="https://doi.org/10.1021/acs.jmedchem.1c00086" target="_blank" >https://doi.org/10.1021/acs.jmedchem.1c00086</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acs.jmedchem.1c00086" target="_blank" >10.1021/acs.jmedchem.1c00086</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells

Popis výsledku v původním jazyce

Misfolding of the neuronal protein α-synuclein (αSyn) into amyloid fibrils is involved in the development of Parkinson’s disease (PD), and inhibition of this process is considered to be a promising therapeutic approach. In this work, we engineered protein inhibitors that bind to fibrils with higher affinity than the monomeric αSyn. They were developed based on the recent structural data of the αSyn fibrils and were shown to prevent fibril elongation upon binding to fibril ends. These inhibitors are highly selective to the misfolded αSyn, nontoxic, and active in cytosol in small concentrations. The best-performing inhibitor shows IC50 ∼10 nM in a cell-based assay, which corresponds to the ∼1:60 molar ratio to αSyn. It can suppress the formation of αSyn aggregates in cells that can be potentially used to slow down the spreading of the pathological aggregates from cell to cell during the course of the PD.

Název v anglickém jazyce

Rationally Designed Protein-Based Inhibitor of α-Synuclein Fibrillization in Cells

Popis výsledku anglicky

Misfolding of the neuronal protein α-synuclein (αSyn) into amyloid fibrils is involved in the development of Parkinson’s disease (PD), and inhibition of this process is considered to be a promising therapeutic approach. In this work, we engineered protein inhibitors that bind to fibrils with higher affinity than the monomeric αSyn. They were developed based on the recent structural data of the αSyn fibrils and were shown to prevent fibril elongation upon binding to fibril ends. These inhibitors are highly selective to the misfolded αSyn, nontoxic, and active in cytosol in small concentrations. The best-performing inhibitor shows IC50 ∼10 nM in a cell-based assay, which corresponds to the ∼1:60 molar ratio to αSyn. It can suppress the formation of αSyn aggregates in cells that can be potentially used to slow down the spreading of the pathological aggregates from cell to cell during the course of the PD.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

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

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

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

Název periodika

Journal of Medicinal Chemistry

ISSN

0022-2623

e-ISSN

1520-4804

Svazek periodika

64

Číslo periodika v rámci svazku

10

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

11

Strana od-do

6827-6837

Kód UT WoS článku

000657351500023

EID výsledku v databázi Scopus

2-s2.0-85106523673