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Proc Natl Acad Sci U S A
. 2023 Jun 27;120(26):e2303292120.
doi: 10.1073/pnas.2303292120. Epub 2023 Jun 20. A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein
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
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.
. 2023 Jun 27;120(26):e2303292120.
doi: 10.1073/pnas.2303292120. Epub 2023 Jun 20. A broad-spectrum macrocyclic peptide inhibitor of the SARS-CoV-2 spike protein
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
- PMID: 37339194
- DOI: 10.1073/pnas.2303292120
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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