Oral Presentation International Peptide Symposium 2023

Biocompatible (Bi)cyclisation of Peptides (#114)

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

Constrained peptides fill an important area of chemical space between small molecule therapies and larger antibodies. Noncanonical modifications such as (bi)cyclisation can (i) enhance metabolic stability by greater resistance towards proteolysis, (ii) promote biological uptake across cell membranes, and (iii) decrease the entropic penalty of binding by locking the peptide in the active conformation.

We developed various unnatural amino acids functionalised with cyanopyridine and 1,2-aminothiol groups that can be directly incorporated into peptides using solid-phase peptide synthesis.1,2 Cyclisation and stapling reactions proceed under biocompatible conditions in presence of protein drug targets to identify high-affinity peptide ligands. Importantly, these amino acids can also be charged onto tRNA enabling their use in selective protein modification and genetically encoded (bi)cyclic peptide libraries.3,4

Bicyclic peptides offer even greater conformational rigidity, metabolic stability, and antibody-like affinity and specificity. We explored the reaction between 1,2-aminothiols and 2,6-dicyanopyridine to establish a biocompatible, selective, and catalyst-free pathway to access bicyclic peptides, which displayed plasma stability, conformational preorganisation, and high target affinity.5 We are even able to selectively construct tricyclic peptides using this biocompatible toolbox.

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 bicyclic peptides for biochemical screening assays.6 We also developed peptide-bismuth bicycles that are able to penetrate mammalian cells as a new type of efficient cell-penetrating peptides.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.