De novo design of picomolar SARS-CoV-2 miniprotein inhibitors.
Amino Acid Sequence
Angiotensin-Converting Enzyme 2
Animals
Antiviral Agents
/ chemistry
Betacoronavirus
/ drug effects
Binding Sites
COVID-19
Chlorocebus aethiops
Coronavirus Infections
Cryoelectron Microscopy
Drug Design
Molecular Docking Simulation
Pandemics
Peptidyl-Dipeptidase A
/ chemistry
Pneumonia, Viral
Protein Binding
/ drug effects
SARS-CoV-2
Spike Glycoprotein, Coronavirus
/ antagonists & inhibitors
Vero Cells
Journal
Science (New York, N.Y.)
ISSN: 1095-9203
Titre abrégé: Science
Pays: United States
ID NLM: 0404511
Informations de publication
Date de publication:
23 10 2020
23 10 2020
Historique:
received:
24
07
2020
accepted:
03
09
2020
pubmed:
11
9
2020
medline:
18
11
2020
entrez:
10
9
2020
Statut:
ppublish
Résumé
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
Identifiants
pubmed: 32907861
pii: science.abd9909
doi: 10.1126/science.abd9909
pmc: PMC7857403
doi:
Substances chimiques
Antiviral Agents
0
Spike Glycoprotein, Coronavirus
0
spike protein, SARS-CoV-2
0
Peptidyl-Dipeptidase A
EC 3.4.15.1
ACE2 protein, human
EC 3.4.17.23
Angiotensin-Converting Enzyme 2
EC 3.4.17.23
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
426-431Subventions
Organisme : NIAID NIH HHS
ID : R01 AI140245
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM120553
Pays : United States
Organisme : NIH HHS
ID : S10 OD023476
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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