Discovery of Dual A beta/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Drosophila Model of Alzheimer's Disease
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00179906%3A_____%2F22%3A10458092" target="_blank" >RIV/00179906:_____/22:10458092 - isvavai.cz</a>
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=CwbOjUAU0v" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=CwbOjUAU0v</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1021/acschemneuro.2c00357" target="_blank" >10.1021/acschemneuro.2c00357</a>
Alternative languages
Result language
angličtina
Original language name
Discovery of Dual A beta/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Drosophila Model of Alzheimer's Disease
Original language description
Alzheimer's disease (AD), the most common type of dementia, currently represents an extremely challenging and unmet medical need worldwide. Amyloid-beta (A beta) and Tau proteins are prototypical AD hallmarks, as well as validated drug targets. Accumulating evidence now suggests that they synergistically contribute to disease pathogenesis. This could not only help explain negative results from anti-A beta clinical trials but also indicate that therapies solely directed at one of them may have to be reconsidered. Based on this, herein, we describe the development of a focused library of 2,4-thiazolidinedione (TZD)-based bivalent derivatives as dual A beta and Tau aggregation inhibitors. The aggregating activity of the 24 synthesized derivatives was tested in intact Escherichia coli cells over-expressing A beta 42 and Tau proteins. We then evaluated their neuronal toxicity and ability to cross the blood-brain barrier (BBB), together with the in vitro interaction with the two isolated proteins. Finally, the most promising (most active, nontoxic, and BBB-permeable) compounds 22 and 23 were tested in vivo, in a Drosophila melanogaster model of AD. The carbazole derivative 22 (20 mu M) showed extremely encouraging results, being able to improve both the lifespan and the climbing abilities of A beta 4 2 expressing flies and generating a better outcome than doxycycline (50 mu M). Moreover, 22 proved to be able to decrease A beta 4 2 aggregates in the brains of the flies. We conclude that bivalent small molecules based on 22 deserve further attention as hits for dual A beta/Tau aggregation inhibition in AD.
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
30104 - Pharmacology and pharmacy
Result continuities
Project
<a href="/en/project/EF18_069%2F0010054" target="_blank" >EF18_069/0010054: IT4Neuro(degeneration)</a><br>
Continuities
P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)
Others
Publication year
2022
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
—
Volume of the periodical
13
Issue of the periodical within the volume
23
Country of publishing house
US - UNITED STATES
Number of pages
16
Pages from-to
nestrankovano
UT code for WoS article
000894025200001
EID of the result in the Scopus database
2-s2.0-85143440253