ORCID Profile
0000-0002-5298-9186
Current Organisation
University of Tokyo
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Publisher: Wiley
Date: 27-12-2022
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 ( K i app =1.5 nM). Subsequent derivatization delivered a biotinylated derivative that enabled one‐step affinity purification of OGT from complex s les. The high potency and novel mechanism of action of these OGT ligands should enable new approaches to elucidate the specificity and regulation of OGT.
Publisher: American Chemical Society (ACS)
Date: 28-05-2021
Publisher: American Chemical Society (ACS)
Date: 24-04-2020
DOI: 10.1021/JACS.0C03152
Publisher: Cold Spring Harbor Laboratory
Date: 04-12-2020
DOI: 10.1101/2020.12.03.410779
Abstract: The Retromer complex (Vps35-Vps26-Vps29) is essential for endosomal membrane trafficking and signalling. Mutations in Retromer cause late-onset Parkinson’s disease, while viral and bacterial pathogens can hijack the complex during cellular infection. To modulate and probe its function we have created a novel series of macrocyclic peptides that bind Retromer with high affinity and specificity. Crystal structures show the majority of cyclic peptides bind to Vps29 via a Pro-Leu-containing sequence, structurally mimicking known interactors such as TBC1D5, and blocking their interaction with Retromer in vitro and in cells. By contrast, macrocyclic peptide RT-L4 binds Retromer at the Vps35-Vps26 interface and is a more effective molecular chaperone than reported small molecules, suggesting a new therapeutic avenue for targeting Retromer. Finally, tagged peptides can be used to probe the cellular localisation of Retromer and its functional interactions in cells, providing novel tools for studying Retromer function.
Publisher: American Chemical Society (ACS)
Date: 23-09-2020
Publisher: Royal Society of Chemistry (RSC)
Date: 2018
DOI: 10.1039/C8SC00286J
Abstract: Tight, non-active site binding cyclic peptides are promising affinity reagents for studying proteins and their interactions.
Publisher: Proceedings of the National Academy of Sciences
Date: 12-10-2020
Abstract: Large DNA-encoded libraries of cyclic peptides are emerging as powerful sources of molecules to tackle challenging drug targets. The structural and functional ersity contained within these libraries is, however, little explored. Here we demonstrate that one such library contains members that use unexpectedly erse mechanisms to recognize the same surface on the same target proteins with high affinity and specificity. This range of binding modes is much larger than observed in natural ligands of the same proteins, demonstrating the power and versatility of the technology. Our data also reveal opportunities for the development of more sophisticated approaches to achieving specificity when trying to selectively target one member of a family of closely related proteins.
Publisher: American Chemical Society (ACS)
Date: 11-2021
DOI: 10.1021/JACS.1C07574
Abstract: Cyclotides are plant-derived peptides with complex structures shaped by their head-to-tail cyclic backbone and cystine knot core. These structural features underpin the native bioactivities of cyclotides, as well as their beneficial properties as pharmaceutical leads, including high proteolytic stability and cell permeability. However, their inherent structural complexity presents a challenge for cyclotide engineering, particularly for accessing libraries of sufficient chemical ersity to design potent and selective cyclotide variants. Here, we report a strategy using mRNA display enabling us to select potent cyclotide-based FXIIa inhibitors from a library comprising more than 10
Publisher: Wiley
Date: 27-12-2022
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 ( K i app =1.5 nM). Subsequent derivatization delivered a biotinylated derivative that enabled one‐step affinity purification of OGT from complex s les. The high potency and novel mechanism of action of these OGT ligands should enable new approaches to elucidate the specificity and regulation of OGT.
Location: United States of America
Location: United States of America
No related grants have been discovered for Hiroaki Suga.