Poster Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Discovery of cyclic peptide ligands to the SARS-CoV-2 spike protein using mRNA display (#132)

Alexander R Norman 1 2 , Charlotte Franck 1 2 , Mary Christie 3 , Paige M E Hawkins 2 4 , Karishma Patel 3 , Anneliese S Ashhurst 2 4 5 6 , Anupriya Aggarwal 7 , Jason K K Low 3 , Rezwan Siddiquee 3 , Caroline L Ashley 5 , Megan Steain 5 , James A Triccas 5 , Stuart Turville 7 , Joel P Mackay 3 , Toby Passioura 3 , Richard J Payne 1 2
  1. School of Chemistry, The University of Sydney, Sydney, NSW, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney, NSW, Australia
  3. School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia
  4. University of Sydney, The University Of Sydney, NSW, Australia
  5. Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  6. Tuberculosis Research Program, Centenary Institute, The University of Sydney, Sydney, NSW, Australia
  7. The Kirby Institute, University of New South Wales, Sydney, NSW, Australia

The COVID-19 pandemic, caused by infection with the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has had an enormous impact on the global population. At the time of writing, there have been over 396 million confirmed cases and more than 5.7 million deaths worldwide as a result of SARS-CoV-2 infection.1 A global research effort has focused on the development of vaccines, antiviral drugs and diagnostic agents to prevent, treat and identify infection of this novel coronavirus.  Viral infection of SARS-CoV-2 is primarily initiated by the favourable interaction between the cell-surface angiotensin converting enzyme 2 (ACE2) and the receptor binding domain (RBD) of the viral spike protein.2 The spike protein is therefore an obvious target in the development of novel vaccine candidates and potential antiviral agents.

This poster will detail our recently published work on the development of high affinity ligands for the receptor binding domain of the SARS-CoV-2 spike protein through the harnessing of RaPID mRNA display technology.5 Identifying several lead compounds with dissociation constants as low as 15 nM, we were able to develop a highly sensitive detection assay for the SARS-CoV-2 virus. Obtaining a co-crystal structure of our lead compound bound to the receptor binding domain also unveiled a new cryptic binding site.

  1. World Health Organisation, covid19.who.int, last accessed on 09/02/2022
  2. Q. Wang, et al. Cell., 2020, 181 (4), 894.
  3. J. Shang, et al. Nature., 2020, 581 (7807), 221.
  4. V. Monteil, et al Cell., 2020, 181 (4), 905.
  5. A. R. Norman, et al. ACS Cent. Sci., 2021, 7, 1001.