De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is decorated with spikes, and viral entry into cells is initiated when these spikes bind to the host angiotensin-converting enzyme 2 (ACE2) receptor. Many monoclonal antibody therapies in development target the spike proteins. Cao et al. d...
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| Published in | Science (American Association for the Advancement of Science) Vol. 370; no. 6515; pp. 426 - 431 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
The American Association for the Advancement of Science
23.10.2020
American Association for the Advancement of Science |
| Subjects | |
| Online Access | Get full text |
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| Abstract | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is decorated with spikes, and viral entry into cells is initiated when these spikes bind to the host angiotensin-converting enzyme 2 (ACE2) receptor. Many monoclonal antibody therapies in development target the spike proteins. Cao
et al.
designed small, stable proteins that bind tightly to the spike and block it from binding to ACE2. The best designs bind with very high affinity and prevent SARS-CoV-2 infection of mammalian Vero E6 cells. Cryo–electron microscopy shows that the structures of the two most potent inhibitors are nearly identical to the computational models. Unlike antibodies, the miniproteins do not require expression in mammalian cells, and their small size and high stability may allow formulation for direct delivery to the nasal or respiratory system.
Science
, this issue p.
426
Designed miniproteins bind tightly to the SARS-CoV-2 spike protein and prevent binding to the host cell receptor.
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
50
) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC
50
~ 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. |
|---|---|
| AbstractList | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is decorated with spikes, and viral entry into cells is initiated when these spikes bind to the host angiotensin-converting enzyme 2 (ACE2) receptor. Many monoclonal antibody therapies in development target the spike proteins. Cao
et al.
designed small, stable proteins that bind tightly to the spike and block it from binding to ACE2. The best designs bind with very high affinity and prevent SARS-CoV-2 infection of mammalian Vero E6 cells. Cryo–electron microscopy shows that the structures of the two most potent inhibitors are nearly identical to the computational models. Unlike antibodies, the miniproteins do not require expression in mammalian cells, and their small size and high stability may allow formulation for direct delivery to the nasal or respiratory system.
Science
, this issue p.
426
Designed miniproteins bind tightly to the SARS-CoV-2 spike protein and prevent binding to the host cell receptor.
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
50
) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC
50
~ 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. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is decorated with spikes, and viral entry into cells is initiated when these spikes bind to the host angiotensin-converting enzyme 2 (ACE2) receptor. Many monoclonal antibody therapies in development target the spike proteins. Cao et al. designed small, stable proteins that bind tightly to the spike and block it from binding to ACE2. The best designs bind with very high affinity and prevent SARS-CoV-2 infection of mammalian Vero E6 cells. Cryo–electron microscopy shows that the structures of the two most potent inhibitors are nearly identical to the computational models. Unlike antibodies, the miniproteins do not require expression in mammalian cells, and their small size and high stability may allow formulation for direct delivery to the nasal or respiratory system. Science , this issue p. 426 Designed miniproteins bind tightly to the SARS-CoV-2 spike protein and prevent binding to the host cell receptor. 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 50 ) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC 50 ~ 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. 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 (IC50) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC50 ~ 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.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 (IC50) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC50 ~ 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. 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. Miniproteins against SARS-CoV-2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is decorated with spikes, and viral entry into cells is initiated when these spikes bind to the host angiotensin-converting enzyme 2 (ACE2) receptor. Many monoclonal antibody therapies in development target the spike proteins. Cao et al. designed small, stable proteins that bind tightly to the spike and block it from binding to ACE2. The best designs bind with very high affinity and prevent SARS-CoV-2 infection of mammalian Vero E6 cells. Cryo–electron microscopy shows that the structures of the two most potent inhibitors are nearly identical to the computational models. Unlike antibodies, the miniproteins do not require expression in mammalian cells, and their small size and high stability may allow formulation for direct delivery to the nasal or respiratory system.Science, this issue p. 426Targeting 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 (IC50) values between 24 picomolar and 35 nanomolar. The most potent, with new binding modes, are 56- and 64-residue proteins (IC50 ~ 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. |
| Author | Coventry, Brian Strauch, Eva-Maria Chen, Rita E. Baker, David Veesler, David Diamond, Michael S. Carter, Lauren Walls, Alexandra C. Goreshnik, Inna Miller, Lauren Case, James Brett Stewart, Lance Park, Young-Jun Cao, Longxing Kozodoy, Lisa |
| Author_xml | – sequence: 1 givenname: Longxing orcidid: 0000-0003-4002-3648 surname: Cao fullname: Cao, Longxing organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA – sequence: 2 givenname: Inna surname: Goreshnik fullname: Goreshnik, Inna organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA – sequence: 3 givenname: Brian orcidid: 0000-0002-6910-6255 surname: Coventry fullname: Coventry, Brian organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Molecular Engineering Graduate Program, University of Washington, Seattle, WA 98195, USA – sequence: 4 givenname: James Brett orcidid: 0000-0001-7331-5511 surname: Case fullname: Case, James Brett organization: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 5 givenname: Lauren orcidid: 0000-0001-5935-4549 surname: Miller fullname: Miller, Lauren organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA – sequence: 6 givenname: Lisa surname: Kozodoy fullname: Kozodoy, Lisa organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA – sequence: 7 givenname: Rita E. surname: Chen fullname: Chen, Rita E. organization: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 8 givenname: Lauren orcidid: 0000-0002-9837-9068 surname: Carter fullname: Carter, Lauren organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA – sequence: 9 givenname: Alexandra C. orcidid: 0000-0002-9636-8330 surname: Walls fullname: Walls, Alexandra C. organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA – sequence: 10 givenname: Young-Jun surname: Park fullname: Park, Young-Jun organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA – sequence: 11 givenname: Eva-Maria orcidid: 0000-0001-7382-747X surname: Strauch fullname: Strauch, Eva-Maria organization: Department of Pharmaceutical and Biomedical Sciences, University of Georgia, Athens, GA 30602, USA – sequence: 12 givenname: Lance orcidid: 0000-0003-4264-5125 surname: Stewart fullname: Stewart, Lance organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA – sequence: 13 givenname: Michael S. orcidid: 0000-0002-8791-3165 surname: Diamond fullname: Diamond, Michael S. organization: Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA., The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, Washington University School of Medicine, St. Louis, MO 63110, USA – sequence: 14 givenname: David orcidid: 0000-0002-6019-8675 surname: Veesler fullname: Veesler, David organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA – sequence: 15 givenname: David orcidid: 0000-0001-7896-6217 surname: Baker fullname: Baker, David organization: Department of Biochemistry, University of Washington, Seattle, WA 98195, USA., Institute for Protein Design, University of Washington, Seattle, WA 98195, USA., Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195, USA |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/32907861$$D View this record in MEDLINE/PubMed |
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| Snippet | Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is decorated with spikes, and viral entry into cells is initiated when these spikes bind to the... Targeting the interaction between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and the human angiotensin-converting enzyme 2... Miniproteins against SARS-CoV-2Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is decorated with spikes, and viral entry into cells is initiated... |
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| SubjectTerms | ACE2 Affinity Amino Acid Sequence Amino acids Anatomy Angiotensin Angiotensin-Converting Enzyme 2 Animals Antiviral Agents - chemistry Betacoronavirus - drug effects Binding Binding Sites Biochem Cell size Chlorocebus aethiops Computer applications Coronaviridae Coronavirus Infections Coronaviruses COVID-19 Cryoelectron Microscopy Design Drug Design Electron microscopy Enzymes Immunotherapy Inhibitors Mammalian cells Mammals Mathematical models Microscopy Molec Biol Molecular Docking Simulation Monoclonal antibodies Pandemics Peptidyl-dipeptidase A Peptidyl-Dipeptidase A - chemistry Pneumonia, Viral Protein Binding - drug effects Proteins Receptors Respiratory diseases Respiratory system SARS-CoV-2 Severe acute respiratory syndrome coronavirus 2 Spike Glycoprotein, Coronavirus - antagonists & inhibitors Spike Glycoprotein, Coronavirus - chemistry Spike protein Stability Trimers Vero Cells Viral diseases |
| Title | De novo design of picomolar SARS-CoV-2 miniprotein inhibitors |
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