Oral Presentation 9th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2023

Late-stage modification of peptides using cyanopyridine and bismuth chemistry (97740)

Christoph Nitsche 1
  1. Australian National University, Canberra, ACT, Australia

Late-stage modification of peptides opens exciting avenues for drug discovery and chemical biology. Noncanonical modifications can enhance metabolic stability, promote biological uptake across cell membranes, and decrease the entropic penalty of binding to protein targets. If late-stage peptide modifications proceed under biocompatible or even bioorthogonal conditions, they can be directly applied to the selective modification of proteins.

We developed various unnatural amino acids functionalized with cyanopyridine derivatives and 1,2-aminothiol groups that can be directly incorporated into peptides using solid-phase peptide synthesis.1,2 Modifications, such as cyclisation and stapling proceed under biocompatible conditions in presence of proteins. Our amino acids can also be charged onto tRNA enabling their use in selective protein modification and genetically encoded peptide libraries.3,4

We further advanced this chemistry by introducing 2,6-dicyanopyridine into peptide side chains, enabling double modifications that are, for example, useful to construct bicyclic peptide libraries under biocompatible conditions.5 Combining this chemistry with our peptide stapling strategy, we were also able to synthesise tricyclic peptides.

Recently, we introduced bismuth as a selective, stable, rigid, and green reagent for peptide modification. Bismuth represents the smallest “scaffold” ever explored and allows in situ access to constrained peptides for biochemical screening assays.6 Bismuth reacts selectively with three cysteines, and the resulting complexes are stable even in presence of common thiol-based reducing agents like glutathione.7

  1. Morewood, R., Nitsche, C., A Biocompatible Stapling Reaction for in situ Generation of Constrained Peptides, Chem. Sci. 2021, 12, 669–674.
  2. Morewood, R., Nitsche, C., Bioinspired Peptide Stapling Generates Stable Enzyme Inhibitors, Chem. Commun. 2022, 58, 10817–10820.
  3. Abdelkader, E., Qianzhu, H., George, J., Frkic, R., Jackson, C., Nitsche, C., Otting, G., Huber, T., Genetic Encoding of Cyanopyridylalanine for In-Cell Protein Macrocyclization by the Nitrile-Aminothiol Click Reaction, Angew. Chem. Int. Ed. 2022, 61, e202114154.
  4. Liu, M., Morewood, R., Yoshisada, R., Pascha, M. N., Hopstaken, A. J. P., Tarcoveanu, E., Poole, D. A., de Haan, C. A. M., Nitsche, C., Jongkees, S. A. K., An N-Terminal Selective Thiazoline Peptide Macrocyclisation Compatible with mRNA Display and Efficient SPPS, ChemRxiv 2023, 10.26434/chemrxiv-2023-wdbkx.
  5. Ullrich, S., George, J., Coram, A. E., Morewood, R., Nitsche, C., Biocompatible and Selective Generation of Bicyclic Peptides, Angew. Chem. Int. Ed. 2022, 61, e202208400.
  6. Voss, S., Rademann, J., Nitsche, C., Peptide-Bismuth Bicycles: In Situ Access to Stable Constrained Peptides with Superior Bioactivity, Angew. Chem. Int. Ed. 2022, 61, e202113857.
  7. Voss, S., Adair, L. D., Achazi, K., Kim, H., Bergemann, S., Bartenschlager, R., New, E. J., Rademann, J., Nitsche, C., Cell-Penetrating Peptide–Bismuth Bicycles, ChemRxiv 2023, 10.26434/chemrxiv-2023-mgxdm.