Discovery of Dual A beta/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Drosophila Model of Alzheimer's Disease

Kód výsledku v 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>

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

Discovery of Dual A beta/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Drosophila Model of Alzheimer's Disease

Popis výsledku v původním jazyce

Alzheimer&apos;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.

Název v anglickém jazyce

Discovery of Dual A beta/Tau Inhibitors and Evaluation of Their Therapeutic Effect on a Drosophila Model of Alzheimer's Disease

Popis výsledku anglicky

Alzheimer&apos;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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/EF18_069%2F0010054" target="_blank" >EF18_069/0010054: IT4Neuro(degeneration)</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2022

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

—

Svazek periodika

13

Číslo periodika v rámci svazku

23

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

16

Strana od-do

nestrankovano

Kód UT WoS článku

000894025200001

EID výsledku v databázi Scopus

2-s2.0-85143440253