Alteen, Matthew G., Peacock, Hayden, Meek, Richard W. et al. (5 more authors) (2023) Potent De Novo Macrocyclic Peptides That Inhibit O-GlcNAc Transferase through an Allosteric Mechanism. Angewandte Chemie - International Edition. e202215671. ISSN 1433-7851
Abstract
Glycosyltransferases are a superfamily of enzymes that are notoriously difficult to inhibit. Here we apply an mRNA display technology integrated with genetic code reprogramming, referred to as the RaPID (random non-standard peptides integrated discovery) system, to identify macrocyclic peptides with high binding affinities for O-GlcNAc transferase (OGT). These macrocycles inhibit OGT activity through an allosteric mechanism that is driven by their binding to the tetratricopeptide repeats of OGT. Saturation mutagenesis in a maturation screen using 39 amino acids, including 22 non-canonical residues, led to an improved unnatural macrocycle that is ≈40 times more potent than the parent compound (Kiapp=1.5 nM). Subsequent derivatization delivered a biotinylated derivative that enabled one-step affinity purification of OGT from complex samples. The high potency and novel mechanism of action of these OGT ligands should enable new approaches to elucidate the specificity and regulation of OGT.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Funding Information: This work was supported by GlycoNet, the Canadian Glycomics Network (CD‐1), the Canadian Cancer Society Research Institute (CCSRI‐706825), and the Canadian Institutes of Health Research (PJT‐156202) to D.J.V. and the Japan Society for the Promotion of Science (JSPS) Grant‐in‐Aid for Specially Promoted Research (JP20H05618) to H.S. G.J.D. thanks the Royal Society for the Ken Murray Research Professorship and R.W.M. for the associated PDRA funding (RP\EA\180016). D.J.V. thanks the Canada Research Chairs program for support as a Tier I CRC in Chemical Biology. Funding Information: This work was supported by GlycoNet, the Canadian Glycomics Network (CD-1), the Canadian Cancer Society Research Institute (CCSRI-706825), and the Canadian Institutes of Health Research (PJT-156202) to D.J.V. and the Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Specially Promoted Research (JP20H05618) to H.S. G.J.D. thanks the Royal Society for the Ken Murray Research Professorship and R.W.M. for the associated PDRA funding (RP\EA\180016). D.J.V. thanks the Canada Research Chairs program for support as a Tier I CRC in Chemical Biology. Publisher Copyright: © 2022 Wiley-VCH GmbH. This is an author-produced version of the published paper. Uploaded in accordance with the publisher’s self-archiving policy. Further copying may not be permitted; contact the publisher for details |
Keywords: | Allosteric Inhibitor,Glycosyltransferase,mRNA Display,O-GlcNAc,Peptide Macrocycle |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Chemistry (York) |
Funding Information: | Funder Grant number THE ROYAL SOCIETY RP\EA\180016 THE ROYAL SOCIETY RSRP\R\210004 |
Depositing User: | Pure (York) |
Date Deposited: | 22 Feb 2023 16:10 |
Last Modified: | 02 Apr 2025 23:25 |
Published Version: | https://doi.org/10.1002/anie.202215671 |
Status: | Published |
Refereed: | Yes |
Identification Number: | 10.1002/anie.202215671 |
Related URLs: | |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:196718 |
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