Thio-linked UDP-peptide conjugates as O-GlcNAc transferase inhibitors

Karim Rafie, Andrii Gorelik, Riccardo Trapannone, Vladimir Borodkin (Lead / Corresponding author), Daan Van Aalten (Lead / Corresponding author)

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    29 Citations (Scopus)
    183 Downloads (Pure)


    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 languageEnglish
    Pages (from-to)1834-1840
    Number of pages7
    JournalBioconjugate Chemistry
    Issue number6
    Early online date3 May 2018
    Publication statusPublished - 20 Jun 2018

    ASJC Scopus subject areas

    • Biotechnology
    • Bioengineering
    • Biomedical Engineering
    • Pharmacology
    • Pharmaceutical Science
    • Organic Chemistry


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