7-Methoxytacrine and 2-Aminobenzothiazole Heterodimers: Structure-Mechanism Relationship of Amyloid Inhibitors Based on Rational Design
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
7-Methoxytacrine and 2-Aminobenzothiazole Heterodimers: Structure-Mechanism Relationship of Amyloid Inhibitors Based on Rational Design
Original language description
The formation and accumulation of amyloid aggregates are the phenomena that accompany amyloidoses, which are currently untreatable and include Alzheimer's and Parkinson'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's ability to prevent this interaction by allowing the BTZ part of the heterodimer to bind more effectively, increasing the compound'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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30107 - Medicinal chemistry
Result continuities
Project
—
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
ACS Chemical Neuroscience
ISSN
1948-7193
e-ISSN
1948-7193
Volume of the periodical
11
Issue of the periodical within the volume
5
Country of publishing house
US - UNITED STATES
Number of pages
15
Pages from-to
715-729
UT code for WoS article
000518702400005
EID of the result in the Scopus database
2-s2.0-85081148072