2. Academic Validation
  3. A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein

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

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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