Structural Optimization of Inhibitors of α-Synuclein Fibril Growth: Affinity to the Fibril End as a Crucial Factor

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F20%3A00518337" target="_blank" >RIV/61388963:_____/20:00518337 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11310/20:10403758

Result on the web

<a href="https://www.sciencedirect.com/science/article/abs/pii/S0022283619306849?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/abs/pii/S0022283619306849?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.jmb.2019.11.019" target="_blank" >10.1016/j.jmb.2019.11.019</a>

Result language

angličtina

Original language name

Structural Optimization of Inhibitors of α-Synuclein Fibril Growth: Affinity to the Fibril End as a Crucial Factor

Original language description

Background: Misfolding of the neuronal protein α-synuclein into amyloid fibrils is a pathological hallmark of Parkinson’s disease, a neurodegenerative disorder that has no cure. Inhibition of the fibril growth is considered a promising therapeutic approach. However, the majority of the existing inhibitors are either unspecific or work at high micromolar concentrations. Earlier we created a protein-based inhibitor of α-synuclein fibril growth that consists of an α-synuclein moiety and a bulky group. It specifically binds to α-synuclein fibril ends and blocks them by creating steric hindrance to subsequent monomer binding. Results: In this work, we prepared a series of inhibitors with modified α-synuclein moieties and bulky groups of different structure, size and position. We studied the structure-activity relationship of these inhibitors and optimized them by improving affinity to the fibril end and blocking efficiency. The inhibitors were tested in a Thioflavin T-based kinetic assay, and their affinity to the fibril ends was measured by fluorescence anisotropy. We showed that decrease in electrostatic repulsion between inhibitor and fibril end improved the inhibitor efficiency. Inhibitors with rigid β-sheet-rich bulky groups bind to fibril ends stronger than monomeric α-synuclein and therefore have a high inhibition efficiency, showing a linear correlation between Kd and IC50. Significance: We determined which properties of inhibitor molecules are the most important for good performance and found that the affinity of an inhibitor to the fibril end is a key feature that determines its inhibition efficiency. Applying this knowledge, we improved existing inhibitors and reached IC50 value of 300 nM.

Czech name

—

Czech description

—

Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10608 - Biochemistry and molecular biology

Project

<a href="/en/project/GJ18-06255Y" target="_blank" >GJ18-06255Y: New strategy for inhibition of amyloid fibril formation</a><br>

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2020

Confidentiality

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

Name of the periodical

Journal of Molecular Biology

ISSN

0022-2836

e-ISSN

—

Volume of the periodical

432

Issue of the periodical within the volume

4

Country of publishing house

GB - UNITED KINGDOM

Number of pages

11

Pages from-to

967-977

UT code for WoS article

000518867100013

EID of the result in the Scopus database

2-s2.0-85078527483