Pingitore, Valeria;
Martínez-Bailén, Macarena;
Carmona, Ana T;
Mészáros, Zuzana;
Kulik, Natalia;
Slámová, Kristýna;
Křen, Vladimír;
... Moreno-Vargas, Antonio J; + view all
(2022)
Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars.
Bioorganic Chemistry
, 120
, Article 105650. 10.1016/j.bioorg.2022.105650.
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Abstract
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 β-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 β-N-acetylhexosaminidase B (hHexB) and human nucleocytoplasmic β-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 × 104 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.
| Type: | Article |
|---|---|
| Title: | Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.bioorg.2022.105650 |
| Publisher version: | https://doi.org/10.1016/j.bioorg.2022.105650 |
| Language: | English |
| Additional information: | © 2022 The Author(s). Published by Elsevier Inc. under a Creative Commons license (https://creativecommons.org/licenses/by-nc-nd/4.0/). |
| Keywords: | Iminosugars, Click reaction, Glycosidase inhibitors, Hexosaminidases, Multivalency, In situ screening |
| UCL classification: | UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine > Wolfson Inst for Biomedical Research UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Medicine |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10156440 |
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