A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein
Publication date
2023-02-28
Authors
Thijssen, Vito
Hurdiss, Daniel L
Debski-Antoniak, Oliver J.
Spence, Matthew A.
Franck, Charlotte
Norman, Alexander
Aggarwal, Anupriya
Mokiem, Nadia J
Dongen, David A. A. van
Vermeir, Stein W.
Editors
Advisors
Supervisors
Document Type
/dk/atira/pure/researchoutput/researchoutputtypes/workingpaper/preprint
Metadata
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License
cc_by_nc_nd
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 mRNA display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-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 ACE2 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
SDG 3 - Good Health and Well-being
Citation
Thijssen, V, Hurdiss, D L, Debski-Antoniak, O J, Spence, M A, Franck, C, Norman, A, Aggarwal, A, Mokiem, N J, Dongen, D A A V, Vermeir, S W, Liu, M, Li, W, Chatziandreou, M, Donselaar, T, Du, W, Drulyte, I, Bosch, B-J, Snijder, J, Turville, S, Payne, R J, Jackson, C J, Kuppeveld, F J M V & Jongkees, S A K 2023 'A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein' bioRxiv, pp. 1-27. https://doi.org/10.1101/2022.11.11.516114