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De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
David Baker; Longxing Cao; Inna Goreshnik; Brian Coventry; James Brett Case; Lauren Miller; Lisa Kozodoy; Rita E. Chen; Lauren Carter; Alexandra Walls; Young-Jun Park; Lance Stewart; Michael Diamond; David Veesler.
Afiliação
  • David Baker; University of Washington
  • Longxing Cao; University of Washington
  • Inna Goreshnik; University of Washington
  • Brian Coventry; University of Washington
  • James Brett Case; Washington University School of Medicine
  • Lauren Miller; University of Washington
  • Lisa Kozodoy; University of Washington
  • Rita E. Chen; Washington University School of Medicine
  • Lauren Carter; University of Washington
  • Alexandra Walls; University of Washington
  • Young-Jun Park; University of Washington
  • Lance Stewart; University of Washington
  • Michael Diamond; Washington University School of Medicine
  • David Veesler; University of Washington
Preprint em En | PREPRINT-BIORXIV | ID: ppbiorxiv-234914
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ABSTRACT
We used two approaches to design proteins with shape and chemical complementarity to the receptor binding domain (RBD) of SARS-CoV-2 Spike protein near the binding site for the human ACE2 receptor. Scaffolds were built around an ACE2 helix that interacts with the RBD, or de novo designed scaffolds were docked against the RBD to identify new binding modes. In both cases, designed sequences were optimized first in silico and then experimentally for target binding, folding and stability. Nine designs bound the RBD with affinities ranging from 100pM to 10nM, and blocked bona fide SARS-CoV-2 infection of Vero E6 cells with IC50 values ranging from 35 pM to 35 nM; the most potent of these -- 56 and 64 residue hyperstable proteins made using the second approach -- are roughly six times more potent on a per mass basis (IC50 ~ 0.23 ng/ml) than the best monoclonal antibodies reported thus far. Cryo-electron microscopy structures of the SARS-CoV-2 spike ectodomain trimer in complex with the two most potent minibinders show that the structures of the designs and their binding interactions with the RBD are nearly identical to the computational models, and that all three RBDs in a single Spike protein can be engaged simultaneously. These hyperstable minibinders provide promising starting points for new SARS-CoV-2 therapeutics, and illustrate the power of computational protein design for rapidly generating potential therapeutic candidates against pandemic threats.
Licença
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Texto completo: 1 Coleções: 09-preprints Base de dados: PREPRINT-BIORXIV Idioma: En Ano de publicação: 2020 Tipo de documento: Preprint
Texto completo: 1 Coleções: 09-preprints Base de dados: PREPRINT-BIORXIV Idioma: En Ano de publicação: 2020 Tipo de documento: Preprint