Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2

Katherine U. Gaynor, Marina Vaysburd, Maximilian A. J. Harman, Anna Albecka, Phillip Jeffrey, Paul Beswick, Guido Papa, Liuhong Chen, Donna Mallery, Brian McGuinness, Katerine Rietschoten, Steven Stanway, Paul Brear, Aleksei Lulla, Katarzyna Ciazynska, Veronica T. Chang, Jo Sharp, Megan Neary, Helen Box, Jo Herriott, Edyta Kijak, Lee Tatham, Eleanor G. Bentley, Parul Sharma, Adam Kirby, Ximeng Han, James P. Stewart, Andrew Owen, John A. G. Briggs, Marko Hyvönen, Michael J. Skynner () and Leo C. James ()
Additional contact information
Katherine U. Gaynor: Portway Building, Granta Park
Marina Vaysburd: Francis Crick Avenue
Maximilian A. J. Harman: Portway Building, Granta Park
Anna Albecka: Francis Crick Avenue
Phillip Jeffrey: Portway Building, Granta Park
Paul Beswick: Portway Building, Granta Park
Guido Papa: Francis Crick Avenue
Liuhong Chen: Portway Building, Granta Park
Donna Mallery: Francis Crick Avenue
Brian McGuinness: Portway Building, Granta Park
Katerine Rietschoten: Portway Building, Granta Park
Steven Stanway: Portway Building, Granta Park
Paul Brear: University of Cambridge
Aleksei Lulla: University of Cambridge
Katarzyna Ciazynska: Francis Crick Avenue
Veronica T. Chang: Francis Crick Avenue
Jo Sharp: University of Liverpool
Megan Neary: University of Liverpool
Helen Box: University of Liverpool
Jo Herriott: University of Liverpool
Edyta Kijak: University of Liverpool
Lee Tatham: University of Liverpool
Eleanor G. Bentley: University of Liverpool
Parul Sharma: University of Liverpool
Adam Kirby: University of Liverpool
Ximeng Han: University of Liverpool
James P. Stewart: University of Liverpool
Andrew Owen: University of Liverpool
John A. G. Briggs: Francis Crick Avenue
Marko Hyvönen: University of Cambridge
Michael J. Skynner: Portway Building, Granta Park
Leo C. James: Francis Crick Avenue

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-39158-1

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