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

0559207 - MBÚ 2023 RIV US eng J - Journal Article
Pingitore, V. - Martinez-Bailen, M. - Carmona, A. T. - Mészáros, Zuzana - Kulik, Natalia - Slámová, Kristýna - Křen, Vladimír - Bojarová, Pavla - Robina, I. - Moreno-Vargas, A. J.
Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars.
Bioorganic Chemistry. Roč. 120, March 2022 (2022), č. článku 105650. ISSN 0045-2068. E-ISSN 1090-2120
R&D Projects: GA ČR(CZ) GF21-01948L
Institutional support: RVO:61388971
Keywords : Iminosugars * Click reaction * Glycosidase inhibitors * Hexosaminidases * Multivalency * In situ screening
OECD category: Microbiology
Impact factor: 5.1, year: 2022
Method of publishing: Open access
https://www.sciencedirect.com/science/article/pii/S0045206822000554?via%3Dihub

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.
Permanent Link: https://hdl.handle.net/11104/0332674