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Publication Abstract from PubMed

The human Golgi alpha-mannosidase, hGMII, removes two mannose residues from GlcNAc-Man(5)GlcNAc(2) to produce GlcNAcMan(3)GlcNAc(2), the precursor of all complex N-glycans including tumour-associated ones. The natural product GMII inhibitor, swainsonine, blocks processing of cancer-associated N-glycans, but also inhibits the four other human alpha-mannosidases, rendering it unsuitable for clinical use. Our previous structure-guided screening of iminosugar pyrrolidine and piperidine fragments identified two micromolar hGMII inhibitors occupying the enzyme active pockets in adjacent, partially overlapping sites. Here we demonstrate that fusing these fragments yields swainsonine-configured indolizidines featuring a C3-substituent that act as selective hGMII inhibitors. Our structure-guided GMII-selective inhibitor design complements a recent combinatorial approach that yielded similarly configured and substituted indolizidine GMII inhibitors, and holds promise for the potential future development of anti-cancer agents targeting Golgi N-glycan processing.

Structure-guided design of C3-branched swainsonine as potent and selective human Golgi alpha-mannosidase (GMII) inhibitor.,Koemans T, Bennett M, Ferraz MJ, Armstrong Z, Artola M, Aerts JMFG, Codee JDC, Overkleeft HS, Davies GJ Chem Commun (Camb). 2024 Sep 25. doi: 10.1039/d4cc04514a. PMID:39318342^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.