Ribosomal Translation and Display Selection of Cyclic Glycopeptides through Genetic Reprogramming
A robust method for the ribosomal incorporation of glycosyl-amino acids through the flexizyme-mediated reprogramming of initiating AUG codons with glycosyl-dipeptides is described. This reprogramming strategy was applied to <i>in vitro</i> mRNA display for the <i>de novo</i> discovery of α-l-fucosylated cyclic peptide inhibitors of P-selectin with antiplatelet-monocyte aggregation activity, and β-d-N-acetylgalactosamine-containing cyclic glycopeptide agonists of the asialoglycoprotein receptor (ASGPR) with potent lysosome trafficking activity. This work provides a powerful platform for the <i>de novo</i> discovery of glycopeptide ligands and expands genetic reprogramming capabilities to large modifications previously intractable for ribosomal translation.
Authors
- Arthur H. Tang (ORCID: https://orcid.org/0000-0002-1696-0861)
- Daniel Ford (ORCID: https://orcid.org/0000-0002-4419-1553)
- Toby Passioura (ORCID: https://orcid.org/0000-0002-6089-5067)
- James G. Burchfield (ORCID: https://orcid.org/0000-0002-6609-6151)
- Leo Corcilius (ORCID: https://orcid.org/0009-0003-0155-3619)
- Douglas G. Johns (ORCID: https://orcid.org/0000-0002-8726-8514)
- Yichen Zhong (ORCID: https://orcid.org/0000-0002-2644-5329)
- José Perdomo (ORCID: https://orcid.org/0000-0002-1554-708X)
- Lucas Kambanis (ORCID: https://orcid.org/0000-0001-8278-5363)
- Walter Ferreira Becker (ORCID: https://orcid.org/0000-0002-4511-0698)
- Beiyuan Cui (ORCID: https://orcid.org/0000-0002-5743-8607)
- Caitlin E. Clarke-Shepperson
- Christopher Lehmann
- Ka Hin Toby Mak
- Bernardo Cavallazzi Sebold
- Jason Johansen-Leete
- Richard J. Payne
Institutions
- The University of Sydney (AU)
- Australian Research Council (AU)
- Harry Perkins Institute of Medical Research (AU)
- The Heart Research Institute (AU)
- Analytical Services (US)
- Yale University (US)
- ARC Centre of Excellence for Innovations in Peptide and Protein Science (AU)
- Central Clinical Hospital (PL)
Publication Details
- Journal
- Journal of the American Chemical Society
- Published
- 2026-03-04
- DOI
- https://doi.org/10.1021/jacs.5c22682
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 0.00