8AAA

Crystal structure of SARS-CoV-2 S RBD in complex with a stapled peptide

Summary for 8AAA

• Entry DOI: 10.2210/pdb8aaa/pdb
• Descriptor: Spike protein S1, Stapled peptide, 1,1',1''-(1,3,5-triazinane-1,3,5-triyl)tripropan-1-one, ... (4 entities in total)
• Functional Keywords: srbd, stapled peptide, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 2
• Total formula weight: 24092.21

Authors

Brear, P.,Chen, L.,Gaynor, K.,Harman, M.,Dods, R.,Hyvonen, M. (deposition date: 2022-06-30, release date: 2023-06-28, Last modification date: 2024-10-23)

Primary citation

Gaynor, K.U.,Vaysburd, M.,Harman, M.A.J.,Albecka, A.,Jeffrey, P.,Beswick, P.,Papa, G.,Chen, L.,Mallery, D.,McGuinness, B.,Van Rietschoten, K.,Stanway, S.,Brear, P.,Lulla, A.,Ciazynska, K.,Chang, V.T.,Sharp, J.,Neary, M.,Box, H.,Herriott, J.,Kijak, E.,Tatham, L.,Bentley, E.G.,Sharma, P.,Kirby, A.,Han, X.,Stewart, J.P.,Owen, A.,Briggs, J.A.G.,Hyvonen, M.,Skynner, M.J.,James, L.C.
Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.
Nat Commun, 14:3583-3583, 2023

PubMed Abstract: COVID-19 has stimulated the rapid development of new antibody and small molecule therapeutics to inhibit SARS-CoV-2 infection. Here we describe a third antiviral modality that combines the drug-like advantages of both. Bicycles are entropically constrained peptides stabilized by a central chemical scaffold into a bi-cyclic structure. Rapid screening of diverse bacteriophage libraries against SARS-CoV-2 Spike yielded unique Bicycle binders across the entire protein. Exploiting Bicycles' inherent chemical combinability, we converted early micromolar hits into nanomolar viral inhibitors through simple multimerization. We also show how combining Bicycles against different epitopes into a single biparatopic agent allows Spike from diverse variants of concern (VoC) to be targeted (Alpha, Beta, Delta and Omicron). Finally, we demonstrate in both male hACE2-transgenic mice and Syrian golden hamsters that both multimerized and biparatopic Bicycles reduce viraemia and prevent host inflammation. These results introduce Bicycles as a potential antiviral modality to tackle new and rapidly evolving viruses.

PubMed: 37328472
DOI: 10.1038/s41467-023-39158-1

Experimental method

X-RAY DIFFRACTION (1.9 Å)