A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein
Thijssen, Vito; Hurdiss, Daniel L; Debski-Antoniak, Oliver J; Spence, Matthew A; Franck, Charlotte; Norman, Alexander; Aggarwal, Anupriya; Mokiem, Nadia J; van Dongen, David A A; Vermeir, Stein W; Liu, Minglong; Li, Wentao; Chatziandreou, Marianthi; Donselaar, Tim; Du, Wenjuan; Drulyte, Ieva; Bosch, Berend-Jan; Snijder, Joost; Turville, Stuart G; Payne, Richard J; Jackson, Colin J; van Kuppeveld, Frank J M; Jongkees, Seino A K
(2023) Proceedings of the National Academy of Sciences of the United States of America, volume 120, issue 26
(Article)
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
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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.
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Keywords: Cryo-EM, SARS-CoV-2, antivirals, mRNA display, macrocyclic peptides, General
ISSN: 0027-8424
Publisher: National Academy of Sciences
Note: Funding Information: made use of the Dutch national e-infrastructure with the support of the SURF Cooperative using grant no. EINF-2453, awarded to D.L.H. V.T. and S.A.K.J. acknowledge general financial support from the department of Chemical Biology and Drug Discovery at Utrecht University. Utrecht Sequencing Facility is subsidized by the University Medical Center Utrecht, Hubrecht Institute, Utrecht University and The Netherlands X-omics Initiative (NWO project 184.034.019). J.S. is funded by the Dutch Research Council NWO Gravitation 2013 BOO, Institute for Chemical Immunology (ICI; 024.002.009). Funding Information: ACKNOWLEDGMENTS. We thank J. A. W. Kruijtzer for assistance with peptide synthesis, and the Utrecht Sequencing Facility for providing sequencing service and data. We thank C. A. M. de Haan and Y. Lang for advice and technical assistance. This work was partially funded by the Corona Accelerated R&D in Europe (CARE) project. The CARE project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 101005077. The JU receives support from the European Union’s Horizon 2020 Research and Innovation Programme, the European Federation of Pharmaceutical Industries and Associations, the Bill & Melinda Gates Foundation, the Global Health Drug Discovery Institute and the University of Dundee. The content of this publication only reflects the author’s views, and the JU is not responsible for any use that may be made of the information it contains. R.J.P. and C.J.J. received support from Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science. This work Publisher Copyright: Copyright © 2023 the Author(s).
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