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Thio-Linked UDP-Peptide Conjugates as O-GlcNAc Transferase Inhibitors.

ABSTRACT: O-GlcNAc transferase (OGT) is an essential glycosyltransferase that installs the O-GlcNAc post-translational 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 photoinitiated 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 ?M) inhibits the OGT activity in HeLa cell lysates. Linear fusions of this conjugate with cell penetrating peptides were explored as prototypes of cell-penetrant OGT 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.

SUBMITTER: Rafie K

PROVIDER: S-EPMC6016062 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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Thio-Linked UDP-Peptide Conjugates as O-GlcNAc Transferase Inhibitors.

Rafie Karim K Gorelik Andrii A Trapannone Riccardo R Borodkin Vladimir S VS van Aalten Daan M F DMF

Bioconjugate chemistry 20180510 6

O-GlcNAc transferase (OGT) is an essential glycosyltransferase that installs the O-GlcNAc post-translational 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 photoinitiated 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 ( K<sub>i</sub> ...[more]

PMID: 29723473

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