A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

  • Proc Natl Acad Sci U S A. 2023 Jun 27;120(26):e2303292120. doi: 10.1073/pnas.2303292120.
Vito Thijssen  1  2 ,  Daniel L Hurdiss  3 ,  Oliver J Debski-Antoniak  3 ,  Matthew A Spence  4 ,  Charlotte Franck  5  6 ,  Alexander Norman  5  6 ,  Anupriya Aggarwal  7 ,  Nadia J Mokiem  8 ,  David A A van Dongen  1  2 ,  Stein W Vermeir  1  2 ,  Minglong Liu  1  2 ,  Wentao Li  3 ,  Marianthi Chatziandreou  3 ,  Tim Donselaar  3 ,  Wenjuan Du  3 ,  Ieva Drulyte  9 ,  Berend-Jan Bosch  3 ,  Joost Snijder  8 ,  Stuart G Turville  7 ,  Richard J Payne  5  6 ,  Colin J Jackson  4  10  11 ,  Frank J M van Kuppeveld  3 ,  Seino A K Jongkees  1  2
Affiliations
  • 1. Chemical Biology and Drug Discovery, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584 CG, the Netherlands.
  • 2. Chemistry and Pharmaceutical Sciences, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, Amsterdam 1081 HV, the Netherlands.
  • 3. Section Virology, Division Infectious Diseases and Immunology, Department of Biomolecular Health Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht 3584 CL, the Netherlands.
  • 4. Research School of Chemistry, Australian National University, Canberra ACT 2601, Australia.
  • 5. School of Chemistry, The University of Sydney, Sydney NSW 2006, Australia.
  • 6. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Sydney, Sydney NSW 2006, Australia.
  • 7. Kirby Institute, Sydney NSW 2052, Australia.
  • 8. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht 3584 CH, the Netherlands.
  • 9. Thermo Fisher Scientific, Materials and Structural Analysis, Eindhoven 5651 GG, the Netherlands.
  • 10. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra ACT 2601, Australia.
  • 11. Australian Research Council Centre of Excellence for Synthetic Biology, Australian National University, Canberra ACT 2601, Australia.
PMID: 37339194 DOI: 10.1073/pnas.2303292120
Abstract

The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, Infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used messenger RNA (mRNA) display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) Wuhan strain Infection and pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor-binding domain, N-terminal domain, and S2 region, distal to the angiotensin-converting enzyme 2 receptor-interaction site. Our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that peptides and potentially Other drug-like molecules can target.

Keywords
Cryo-EM; SARS-CoV-2; antivirals; mRNA display; macrocyclic peptides.
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