7-Methoxytacrine and 2-Aminobenzothiazole Heterodimers: Structure-Mechanism Relationship of Amyloid Inhibitors Based on Rational Design

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F20%3A50020151" target="_blank" >RIV/62690094:18470/20:50020151 - isvavai.cz</a>

Výsledek na webu

<a href="https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.9b00419" target="_blank" >https://pubs.acs.org/doi/pdf/10.1021/acschemneuro.9b00419</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1021/acschemneuro.9b00419" target="_blank" >10.1021/acschemneuro.9b00419</a>

Jazyk výsledku

angličtina

Název v původním jazyce

7-Methoxytacrine and 2-Aminobenzothiazole Heterodimers: Structure-Mechanism Relationship of Amyloid Inhibitors Based on Rational Design

Popis výsledku v původním jazyce

The formation and accumulation of amyloid aggregates are the phenomena that accompany amyloidoses, which are currently untreatable and include Alzheimer&apos;s and Parkinson&apos;s diseases, diabetes mellitus, non-neuropathic lysozyme systemic amyloidosis, and others. One of the very promising therapeutic approaches seems to be an inhibition of amyloid formation and/or clearance of amyloid aggregates. Small molecules have a great potential to interfere with amyloid fibrillation of peptides and polypeptides, which can be improved by connection of cyclic structures into single multicyclic molecules and their dimerization. In our study, we focused on heterodimers consisting of 7-methoxytacrine (7-MEOTA) and 2-aminobenzothiazole (BTZ) parent molecules connected by an aliphatic linker. Using in vitro and in silica methods, we investigated the ability of studied compounds to inhibit the amyloid aggregation of hen egg white lysozyme. Heterodimerization led to significant improvement of inhibitory activity compared to that of the parent molecules. The efficiency of the heterodimers varied; the most effective inhibitor contained the longest linker, eight carbons long. We suggest that binding of a heterodimer to a lysozyme blocks the interaction between the beta-domain and C-helix region essential for the formation of amyloid cross-beta structure. Elongation of the linker ultimately enhances the compound&apos;s ability to prevent this interaction by allowing the BTZ part of the heterodimer to bind more effectively, increasing the compound&apos;s binding affinity, and also by greater steric obstruction. This study represents an important contribution to the recent rational design of potential lead small molecules with anti-amyloid properties, and the heterodimers studied are prospective candidates for the treatment of systemic lysozyme amyloidosis and other amyloid-related diseases.

Název v anglickém jazyce

7-Methoxytacrine and 2-Aminobenzothiazole Heterodimers: Structure-Mechanism Relationship of Amyloid Inhibitors Based on Rational Design

Popis výsledku anglicky

The formation and accumulation of amyloid aggregates are the phenomena that accompany amyloidoses, which are currently untreatable and include Alzheimer&apos;s and Parkinson&apos;s diseases, diabetes mellitus, non-neuropathic lysozyme systemic amyloidosis, and others. One of the very promising therapeutic approaches seems to be an inhibition of amyloid formation and/or clearance of amyloid aggregates. Small molecules have a great potential to interfere with amyloid fibrillation of peptides and polypeptides, which can be improved by connection of cyclic structures into single multicyclic molecules and their dimerization. In our study, we focused on heterodimers consisting of 7-methoxytacrine (7-MEOTA) and 2-aminobenzothiazole (BTZ) parent molecules connected by an aliphatic linker. Using in vitro and in silica methods, we investigated the ability of studied compounds to inhibit the amyloid aggregation of hen egg white lysozyme. Heterodimerization led to significant improvement of inhibitory activity compared to that of the parent molecules. The efficiency of the heterodimers varied; the most effective inhibitor contained the longest linker, eight carbons long. We suggest that binding of a heterodimer to a lysozyme blocks the interaction between the beta-domain and C-helix region essential for the formation of amyloid cross-beta structure. Elongation of the linker ultimately enhances the compound&apos;s ability to prevent this interaction by allowing the BTZ part of the heterodimer to bind more effectively, increasing the compound&apos;s binding affinity, and also by greater steric obstruction. This study represents an important contribution to the recent rational design of potential lead small molecules with anti-amyloid properties, and the heterodimers studied are prospective candidates for the treatment of systemic lysozyme amyloidosis and other amyloid-related diseases.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30107 - Medicinal chemistry

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2020

Kód důvěrnosti údajů

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

Název periodika

ACS Chemical Neuroscience

ISSN

1948-7193

e-ISSN

1948-7193

Svazek periodika

11

Číslo periodika v rámci svazku

5

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

715-729

Kód UT WoS článku

000518702400005

EID výsledku v databázi Scopus

2-s2.0-85081148072