tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Daniel L Hurdiss[SUP] 3 [/SUP], Oliver J Debski-Antoniak[SUP] 3 [/SUP], Matthew A Spence[SUP] 4 [/SUP], Charlotte Franck[SUP] 5 6 [/SUP], Alexander Norman[SUP] 5 6 [/SUP], Anupriya Aggarwal[SUP] 7 [/SUP], Nadia J Mokiem[SUP] 8 [/SUP], David A A van Dongen[SUP] 1 2 [/SUP], Stein W Vermeir[SUP] 1 2 [/SUP], Minglong Liu[SUP] 1 2 [/SUP], Wentao Li[SUP] 3 [/SUP], Marianthi Chatziandreou[SUP] 3 [/SUP], Tim Donselaar[SUP] 3 [/SUP], Wenjuan Du[SUP] 3 [/SUP], Ieva Drulyte[SUP] 9 [/SUP], Berend-Jan Bosch[SUP] 3 [/SUP], Joost Snijder[SUP] 8 [/SUP], Stuart G Turville[SUP] 7 [/SUP], Richard J Payne[SUP] 5 6 [/SUP], Colin J Jackson[SUP] 4 10 11 [/SUP], Frank J M van Kuppeveld[SUP] 3 [/SUP], Seino A K Jongkees[SUP] 1 2 [/SUP]
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[SUP] 1 2 [/SUP], Daniel L Hurdiss[SUP] 3 [/SUP], Oliver J Debski-Antoniak[SUP] 3 [/SUP], Matthew A Spence[SUP] 4 [/SUP], Charlotte Franck[SUP] 5 6 [/SUP], Alexander Norman[SUP] 5 6 [/SUP], Anupriya Aggarwal[SUP] 7 [/SUP], Nadia J Mokiem[SUP] 8 [/SUP], David A A van Dongen[SUP] 1 2 [/SUP], Stein W Vermeir[SUP] 1 2 [/SUP], Minglong Liu[SUP] 1 2 [/SUP], Wentao Li[SUP] 3 [/SUP], Marianthi Chatziandreou[SUP] 3 [/SUP], Tim Donselaar[SUP] 3 [/SUP], Wenjuan Du[SUP] 3 [/SUP], Ieva Drulyte[SUP] 9 [/SUP], Berend-Jan Bosch[SUP] 3 [/SUP], Joost Snijder[SUP] 8 [/SUP], Stuart G Turville[SUP] 7 [/SUP], Richard J Payne[SUP] 5 6 [/SUP], Colin J Jackson[SUP] 4 10 11 [/SUP], Frank J M van Kuppeveld[SUP] 3 [/SUP], Seino A K Jongkees[SUP] 1 2 [/SUP]
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.