Multivalent bicyclic peptides are an effective antiviral modality that can potently inhibit SARS-CoV-2.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
16 06 2023
16 06 2023
Historique:
received:
08
11
2022
accepted:
26
05
2023
medline:
19
6
2023
pubmed:
17
6
2023
entrez:
16
6
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37328472
doi: 10.1038/s41467-023-39158-1
pii: 10.1038/s41467-023-39158-1
pmc: PMC10275983
doi:
Substances chimiques
Antiviral Agents
0
Peptides
0
Antibodies
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3583Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : Medical Research Council
ID : U105181010
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 223054/Z/21/Z
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 214344/A/18/Z
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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