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Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars
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SYSNO ASEP 0559207 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Discovery of human hexosaminidase inhibitors by in situ screening of a library of mono- and divalent pyrrolidine iminosugars Author(s) Pingitore, V. (ES)
Martinez-Bailen, M. (ES)
Carmona, A. T. (ES)
Mészáros, Zuzana (MBU-M)
Kulik, Natalia (MBU-M) ORCID
Slámová, Kristýna (MBU-M) RID, ORCID
Křen, Vladimír (MBU-M) RID, ORCID
Bojarová, Pavla (MBU-M) ORCID
Robina, I. (ES)
Moreno-Vargas, A. J. (ES)Article number 105650 Source Title Bioorganic Chemistry. - : Elsevier - ISSN 0045-2068
Roč. 120, March 2022 (2022)Number of pages 12 s. Language eng - English Country US - United States Keywords Iminosugars ; Click reaction ; Glycosidase inhibitors ; Hexosaminidases ; Multivalency ; In situ screening Subject RIV CE - Biochemistry OECD category Microbiology R&D Projects GF21-01948L GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support MBU-M - RVO:61388971 UT WOS 000820618400004 EID SCOPUS 85124213415 DOI 10.1016/j.bioorg.2022.105650 Annotation 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. Workplace Institute of Microbiology Contact Eliška Spurná, eliska.spurna@biomed.cas.cz, Tel.: 241 062 231 Year of Publishing 2023 Electronic address https://www.sciencedirect.com/science/article/pii/S0045206822000554?via%3Dihub
Number of the records: 1