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

Vito Thijssen; Daniel L Hurdiss; Oliver J Debski-Antoniak; Matthew A Spence; Charlotte Franck; Alexander Norman; Anupriya Aggarwal; Nadia J Mokiem; David A A van Dongen; Stein W Vermeir; Minglong Liu; Wentao Li; Marianthi Chatziandreou; Tim Donselaar; Wenjuan Du; Ieva Drulyte; Berend-Jan Bosch; Joost Snijder; Stuart G Turville; Richard J Payne; Colin J Jackson; Frank J M van Kuppeveld; Seino A K Jongkees

doi:10.1073/pnas.2303292120

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. Epub 2023 Jun 20.

Authors

Vito Thijssen^{1

2}, Daniel L Hurdiss³, Oliver J Debski-Antoniak³, Matthew A Spence⁴, Charlotte Franck^{5

6}, Alexander Norman^{5

6}, Anupriya Aggarwal⁷, Nadia J Mokiem⁸, David A A van Dongen^{1

2}, Stein W Vermeir^{1

2}, Minglong Liu^{1

2}, Wentao Li³, Marianthi Chatziandreou³, Tim Donselaar³, Wenjuan Du³, Ieva Drulyte⁹, Berend-Jan Bosch³, Joost Snijder⁸, Stuart G Turville⁷, Richard J Payne^{5

6}, Colin J Jackson^{4

10

11}, Frank J M van Kuppeveld³, 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.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19*
Humans
Pandemics / prevention & control
Peptides / pharmacology
SARS-CoV-2* / metabolism
Spike Glycoprotein, Coronavirus / metabolism

Substances

spike protein, SARS-CoV-2
Spike Glycoprotein, Coronavirus
Peptides

Supplementary concepts

SARS-CoV-2 variants