Abstract
O-GlcNAc transferase (OGT) is an essential glycosyltransferase that installs the O-GlcNAc posttranslational modification on the nucleocytoplasmic proteome. We report the development of S-linked UDP-peptide conjugates as potent bisubstrate OGT inhibitors. These compounds were assembled in a modular fashion by photo-initiated thiol-ene conjugation of allyl-UDP and optimal acceptor peptides in which the acceptor serine was replaced with cysteine. The conjugate VTPVC(S-propyl-UDP)TA (Ki = 1.3 µM) inhibits the OGT activity in HeLa cell lysates. Linear fusions of this conjugate with cell penetrating peptides were explored as prototypes of cell-penetrant hOGT inhibitors. A crystal structure of human OGT with the inhibitor revealed mimicry of the interactions seen in the pseudo-Michaelis complex. Furthermore, a fluorophore-tagged derivative of the inhibitor works as a high affinity probe in a fluorescence polarimetry hOGT assay.
Original language | English |
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Pages (from-to) | 1834-1840 |
Number of pages | 7 |
Journal | Bioconjugate Chemistry |
Volume | 29 |
Issue number | 6 |
Early online date | 3 May 2018 |
DOIs | |
Publication status | Published - 20 Jun 2018 |
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van Aalten, Daan
- Gene Regulation and Expression - Professor & Biological Chemistry
Person: Academic