An identification of MARK inhibitors using high throughput MALDI-TOF mass spectrometry

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61989592%3A15110%2F22%3A73612578" target="_blank" >RIV/61989592:15110/22:73612578 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0753332221013366?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0753332221013366?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.biopha.2021.112549" target="_blank" >10.1016/j.biopha.2021.112549</a>

Jazyk výsledku

angličtina

Název v původním jazyce

An identification of MARK inhibitors using high throughput MALDI-TOF mass spectrometry

Popis výsledku v původním jazyce

MAP/micmtubule affinity-regulating kinases (MARKs) were recently identified as potential drug targets for Alzheimer&apos;s disease (AD) due to their role in pathological hyperphosphorylation of tau protein. Hyperphosphorylated tau has decreased affinity for microtubule binding, impairing their stability and associated functions. Destabilization of microtubules in neuronal cells leads to neumdegeneration, and microtubuleunbound tau forms neurofibrillary tangles, one of the primary hallmarks of AD. Many phosphorylation sites of tau protein have been identified, but phosphorylation at Ser(262) , which occurs in early stages of AD, plays a vital role in the pathological hyperphosphorylation of tau. It has been found that Ser(262) is phosphorylated by MARK4, which is currently an intensively studied target for treating Alzheimer&apos;s disease and other neurodegenerative diseases. Our present study aimed to develop a high throughput compatible assay to directly detect MARK enzymatic activity using echoacoustic transfer and MALDI-TOF mass spectrometer. We optimized the assay for all four isoforms of MARK and validated its use for identifying potential inhibitors by the screening of 1280 compounds from the LOPAC (R) 1280 International (Library Of Pharmacologically Active Compounds). Six MARK4 inhibitors with IC50 &lt; 1 mu M were identified. To demonstrate their therapeutic potential, active compounds were further tested for MARK4 selectivity and ability to cross the blood-brain barrier. Lastly, the molecular docking with the most active inhibitors to predict their interaction with MARK4 was performed.

Název v anglickém jazyce

An identification of MARK inhibitors using high throughput MALDI-TOF mass spectrometry

Popis výsledku anglicky

MAP/micmtubule affinity-regulating kinases (MARKs) were recently identified as potential drug targets for Alzheimer&apos;s disease (AD) due to their role in pathological hyperphosphorylation of tau protein. Hyperphosphorylated tau has decreased affinity for microtubule binding, impairing their stability and associated functions. Destabilization of microtubules in neuronal cells leads to neumdegeneration, and microtubuleunbound tau forms neurofibrillary tangles, one of the primary hallmarks of AD. Many phosphorylation sites of tau protein have been identified, but phosphorylation at Ser(262) , which occurs in early stages of AD, plays a vital role in the pathological hyperphosphorylation of tau. It has been found that Ser(262) is phosphorylated by MARK4, which is currently an intensively studied target for treating Alzheimer&apos;s disease and other neurodegenerative diseases. Our present study aimed to develop a high throughput compatible assay to directly detect MARK enzymatic activity using echoacoustic transfer and MALDI-TOF mass spectrometer. We optimized the assay for all four isoforms of MARK and validated its use for identifying potential inhibitors by the screening of 1280 compounds from the LOPAC (R) 1280 International (Library Of Pharmacologically Active Compounds). Six MARK4 inhibitors with IC50 &lt; 1 mu M were identified. To demonstrate their therapeutic potential, active compounds were further tested for MARK4 selectivity and ability to cross the blood-brain barrier. Lastly, the molecular docking with the most active inhibitors to predict their interaction with MARK4 was performed.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

Výsledek vznikl pri realizaci vícero projektů. Více informací v záložce Projekty.

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

BIOMEDICINE &amp; PHARMACOTHERAPY

ISSN

0753-3322

e-ISSN

1950-6007

Svazek periodika

146

Číslo periodika v rámci svazku

February 2022

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

10

Strana od-do

112549

Kód UT WoS článku

000744602000002

EID výsledku v databázi Scopus

2-s2.0-85121204355