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

Exploiting screening technologies to modulate the pharmacodynamic and pharmacokinetic properties of therapeutic peptides (98568)

Kat Harrison 1 2 , Jason Johansen-Leete 1 2 , Sven Ullrich 3 , Sarah E. Fry 1 2 , Rebecca Frkic 3 4 , Ralph Adams 5 , Callum Joyce 5 , Christoph Nitsche 3 , Alex Macpherson 5 , Richard J. Payne 1 2
  1. School of Chemistry, The University of Sydney, Camperdown, NSW, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, NSW, Australia
  3. Research School of Chemistry, Australian National University, Canberra, ACT 2601, Australia
  4. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT , Australia
  5. Early Solutions, UCB Biopharma, Slough, United Kingdom

The advent of DNA encoded libraries and high throughput display methodologies have together revolutionised the discovery and development of therapeutic peptides and proteins. The most widely used of these, phage display, has been successfully used to develop a large number of bioactive peptides and proteins, including the variable domains of antibody-like molecules.1 We exploited phage display to identify novel “knob domains” that bound to human and mouse serum albumin to modulate the pharmacokinetic properties of peptide-knob conjugates.2 This was validated via the conjugation of anti-albumin knob to a potent IL-17A antagonist, HAP, which in isolation is degraded rapidly. Pleasingly, synthetic conjugates of these two biomolecules produced bifunctional molecules with long serum half-lives and exerted potent anti-inflammatory effects.

While this approach is broadly applicable to increase circulating half-life of linear peptides, modern display technologies have been developed for the discovery of macrocyclic peptides that bear intrinsic serum stability. Herein, we describe our use of one such technology, Random nonstandard Peptide Integrated Discovery (RaPID) mRNA display, to discover antiviral peptides targeting SARS-CoV-2.3 An initial screen on a chemically cross-linked SARS-CoV-2 Mpro dimer identified several high-affinity cyclic peptides that were potent inhibitors of the catalytic activity of this essential protease.4 While these peptides exhibited excellent activity against the isolated enzyme, their in vitro antiviral activity against SARS-CoV-2 was hampered by limited cell permeability. To combat this, we rationally designed analogues of our parent inhibitors to improve their cell permeability, and with it, antiviral activity.

  1. Smith, G. P., Petrenko, V. A., Chem. Rev., 97, 391-410 (1997).
  2. Adams, R. et al., Front. Immunol., 14, (2023).
  3. Hipolito, C. J., Suga, H. Curr. Opin. Chem. Biol., 16, 196-203 (2012).
  4. Johansen-Leete, J. et al., Chem. Sci., 2022, 13, 3826-3836 (2023).