Physiologically relevant fluorescent assay for identification of 17β-hydroxysteroid dehydrogenase type 10 inhibitors

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F23%3A50020754" target="_blank" >RIV/62690094:18470/23:50020754 - isvavai.cz</a>

Výsledek na webu

<a href="https://onlinelibrary.wiley.com/doi/10.1111/jnc.15917" target="_blank" >https://onlinelibrary.wiley.com/doi/10.1111/jnc.15917</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1111/jnc.15917" target="_blank" >10.1111/jnc.15917</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Physiologically relevant fluorescent assay for identification of 17β-hydroxysteroid dehydrogenase type 10 inhibitors

Popis výsledku v původním jazyce

Mitochondrial enzyme 17 beta-hydroxysteroid dehydrogenase type 10 (HSD10) is a potential molecular target for treatment of mitochondrial-related disorders such as Alzheimer&apos;s disease (AD). Its over-expression in AD brains is one of the critical factors disturbing the homeostasis of neuroprotective steroids and exacerbating amyloid beta (A beta)-mediated mitochondrial toxicity and neuronal stress. This study was focused on revalidation of the most potent HSD10 inhibitors derived from benzothiazolyl urea scaffold using fluorescent-based enzymatic assay with physiologically relevant substrates of 17 beta-oestradiol and allopregnanolone. The oestradiol-based assay led to the identification of two nanomolar inhibitors (IC50 70 and 346 nM) differing from HSD10 hits revealed from the formerly used assay. Both identified inhibitors were found to be effective also in allopregnanolone-based assay with non-competitive or uncompetitive mode of action. In addition, both inhibitors were confirmed to penetrate the HEK293 cells and they were able to inhibit the HSD10 enzyme in the cellular environment. Both molecules seem to be potential lead structures for further research and development of HDS10 inhibitors.

Název v anglickém jazyce

Physiologically relevant fluorescent assay for identification of 17β-hydroxysteroid dehydrogenase type 10 inhibitors

Popis výsledku anglicky

Mitochondrial enzyme 17 beta-hydroxysteroid dehydrogenase type 10 (HSD10) is a potential molecular target for treatment of mitochondrial-related disorders such as Alzheimer&apos;s disease (AD). Its over-expression in AD brains is one of the critical factors disturbing the homeostasis of neuroprotective steroids and exacerbating amyloid beta (A beta)-mediated mitochondrial toxicity and neuronal stress. This study was focused on revalidation of the most potent HSD10 inhibitors derived from benzothiazolyl urea scaffold using fluorescent-based enzymatic assay with physiologically relevant substrates of 17 beta-oestradiol and allopregnanolone. The oestradiol-based assay led to the identification of two nanomolar inhibitors (IC50 70 and 346 nM) differing from HSD10 hits revealed from the formerly used assay. Both identified inhibitors were found to be effective also in allopregnanolone-based assay with non-competitive or uncompetitive mode of action. In addition, both inhibitors were confirmed to penetrate the HEK293 cells and they were able to inhibit the HSD10 enzyme in the cellular environment. Both molecules seem to be potential lead structures for further research and development of HDS10 inhibitors.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10609 - Biochemical research methods

Projekt

—

Návaznosti

S - Specificky vyzkum na vysokych skolach

Rok uplatnění

2023

Kód důvěrnosti údajů

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

Název periodika

Journal of Neurochemistry

ISSN

0022-3042

e-ISSN

1471-4159

Svazek periodika

167

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

154-167

Kód UT WoS článku

001028310900001

EID výsledku v databázi Scopus

2-s2.0-85165257150