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TitleDe novo design of picomolar SARS-CoV-2 miniprotein inhibitors.
Journal, issue, pagesScience, Vol. 370, Issue 6515, Page 426-431, Year 2020
Publish dateOct 23, 2020
AuthorsLongxing Cao / Inna Goreshnik / Brian Coventry / James Brett Case / Lauren Miller / Lisa Kozodoy / Rita E Chen / Lauren Carter / Alexandra C Walls / Young-Jun Park / Eva-Maria Strauch / Lance Stewart / Michael S Diamond / David Veesler / David Baker /
PubMed AbstractTargeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising ...Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2 (ACE2) receptor is a promising therapeutic strategy. We designed inhibitors using two de novo design approaches. Computer-generated scaffolds were either built around an ACE2 helix that interacts with the spike receptor binding domain (RBD) or docked against the RBD to identify new binding modes, and their amino acid sequences were designed to optimize target binding, folding, and stability. Ten designs bound the RBD, with affinities ranging from 100 picomolar to 10 nanomolar, and blocked SARS-CoV-2 infection of Vero E6 cells with median inhibitory concentration (IC) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC ~ 0.16 nanograms per milliliter). Cryo-electron microscopy structures of these minibinders in complex with the SARS-CoV-2 spike ectodomain trimer with all three RBDs bound are nearly identical to the computational models. These hyperstable minibinders provide starting points for SARS-CoV-2 therapeutics.
External linksScience / PubMed:32907861 / PubMed Central
MethodsEM (single particle)
Resolution2.7 - 3.5 Å
Structure data

22532

7jzl

EMDB-22532, PDB-7jzl:
SARS-CoV-2 spike in complex with LCB1 (2RBDs open)
Method: EM (single particle) / Resolution: 2.7 Å

22533

7jzm

EMDB-22533, PDB-7jzm:
SARS-CoV-2 spike in complex with LCB3 (local refinement of the RBD and LCB3)
Method: EM (single particle) / Resolution: 3.5 Å

22534

7jzn

EMDB-22534, PDB-7jzn:
SARS-CoV-2 spike in complex with LCB3 (2RBDs open)
Method: EM (single particle) / Resolution: 3.1 Å

EMDB-22535:
SARS-CoV-2 spike in complex with LCB3 (3RBDs open)
Method: EM (single particle) / Resolution: 3.2 Å

22574

7jzu

EMDB-22574, PDB-7jzu:
SARS-CoV-2 spike in complex with LCB1 (local refinement of the RBD and LCB1)
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

Source
  • severe acute respiratory syndrome coronavirus 2
  • synthetic construct (others)
  • Severe acute respiratory syndrome-related coronavirus
KeywordsVIRAL PROTEIN / SARS-CoV-2 / COVID-19 / spike glycoprotein / fusion protein / neutralizing antibodies / Structural Genomics / Seattle Structural Genomics Center for Infectious Disease / SSGCID / Inhibitor / Inhibotor

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