Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F22%3A00559207" target="_blank" >RIV/61388971:_____/22:00559207 - isvavai.cz</a>

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0045206822000554?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0045206822000554?via%3Dihub</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.bioorg.2022.105650" target="_blank" >10.1016/j.bioorg.2022.105650</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars

Popis výsledku v původním jazyce

Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of beta-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal beta-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic beta-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 x 10(4) times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A.

Název v anglickém jazyce

Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars

Popis výsledku anglicky

Two libraries of mono- and dimeric pyrrolidine iminosugars were synthesized by CuAAC and (thio)urea-bond-forming reactions from the respective azido/aminohexylpyrrolidine iminosugar precursors. The resulting monomeric and dimeric compounds were screened for inhibition of beta-N-acetylglucosaminidase from Jack beans, the plant ortholog of human lysosomal hexosaminidases. A selection of the best inhibitors of these libraries was then evaluated against human lysosomal beta-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic beta-N-acetylglucosaminidase (hOGA). This evaluation identified a potent (nM) and selective monomeric inhibitor of hOGA (compound 7A) that showed a 6770-fold higher affinity for this enzyme than for hHexB. The corresponding dimeric derivative (compound 9D) further remarkably improved the selectivity in the inhibition of hOGA (2.7 x 10(4) times more selective for hOGA over hHexB) and the inhibition potency (by one order of magnitude). Docking studies were performed to explain the selectivity of inhibition observed in compound 7A.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10606 - Microbiology

Projekt

<a href="/cs/project/GF21-01948L" target="_blank" >GF21-01948L: Nová glykomimetika pro léčbu neurodegenerativních nemocí spojených s pokročilým věkem</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2022

Kód důvěrnosti údajů

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

Název periodika

Bioorganic Chemistry

ISSN

0045-2068

e-ISSN

1090-2120

Svazek periodika

120

Číslo periodika v rámci svazku

March 2022

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

105650

Kód UT WoS článku

000820618400004

EID výsledku v databázi Scopus

2-s2.0-85124213415