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Massively parallel de novo protein design for targeted therapeutics
Open accessAbstract
De novo protein design holds promise for creating small stable proteins with shapes customized to bind therapeutic targets. We describe a massively parallel approach for designing, manufacturing and screening mini-protein binders, integrating large-scale computational design, oligonucleotide synthesis, yeast display screening and next-generation sequencing. We designed and tested 22,660 mini-proteins of 37-43 residues that target influenza haemagglutinin and botulinum neurotoxin B, along with 6,286 control sequences to probe contributions to folding and binding, and identified 2,618 high-affinity binders. Comparison of the binding and non-binding design sets, which are two orders of magnitude larger than any previously investigated, enabled the evaluation and improvement of the computational model. Biophysical characterization of a subset of the binder designs showed that they are extremely stable and, unlike antibodies, do not lose activity after exposure to high temperatures. The designs elicit little or no immune response and provide potent prophylactic and therapeutic protection against influenza, even after extensive repeated dosing.
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“The design of proteins that bind to a specific site on the surface of a target protein using no information other than the three-dimensional structure of the target remains a challenge1–5.”
From Design of protein-binding proteins from the target structure alone (2022) · cites this paper as [1]
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“Most current computational methods used to design proteins that bind to a target surface utilize information derived from structures of the native complex on specific side-chain interactions or protein backbone placements optimal for binding1–3.”
From Design of protein-binding proteins from the target structure alone (2022) · cites this paper as [1]
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“Protein1,5, peptide36 and small-molecule inhibitors37 have been designed to bind to the stem region of group 1 HA and neutralize influenza A viruses, but none recognize the group 2 HA.”
From Design of protein-binding proteins from the target structure alone (2022) · cites this paper as [1]
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Cites
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Molecular Dynamics Simulation for All
Hollingsworth, S. A., & Dror, R. O. (2018) · Neuron · doi:10.1016/j.neuron.2018.08.011 · Cited by 3,522
Watson, J. L., Juergens, D., Bennett, N. R., Trippe, B. L., Yim, J., Eisenach, H. E., Ahern, W., Borst, A. J., Ragotte, R. J., Milles, L. F., et al. (2022) · doi:10.1101/2022.12.09.519842 · Cited by 2,369
Self-citationDe novo design of protein structure and function with RFdiffusion
Watson, J. L., Juergens, D., Bennett, N. R., Trippe, B. L., Yim, J., Eisenach, H. E., Ahern, W., Borst, A. J., Ragotte, R. J., Milles, L. F., et al. (2023) · Nature · doi:10.1038/s41586-023-06415-8 · Cited by 2,325
Self-citationAdvances in protein structure prediction and design
Kuhlman, B., & Bradley, P. (2019) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-019-0163-x · Cited by 806
De novo design of picomolar SARS-CoV-2 miniprotein inhibitors
Cao, L., Goreshnik, I., Coventry, B., Case, J. B., Miller, L., Kozodoy, L., Chen, R. E., Carter, L., Walls, A. C., Park, Y.-J., et al. (2020) · Science · doi:10.1126/science.abd9909 · Cited by 742
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Metadata
- Authors
- Chevalier, A., Silva, D.-A., Rocklin, G. J., Hicks, D. R., Vergara, R., Murapa, P., Bernard, S. M., Zhang, L., Lam, K.-H., Yao, G., Bahl, C. D., Miyashita, S.-I., Goreshnik, I., Fuller, J. T., Koday, M. T., Jenkins, C. M., Colvin, T., Carter, L., Bohn, A., Bryan, C. M., Fernández-Velasco, D. A., Stewart, L., Dong, M., Huang, X., Jin, R., Wilson, I. A., Fuller, D. H., & Baker, D.
- Affiliations
- University of Washington (US)
- Scripps Research Institute (US)
- Chinese Academy of Sciences (CN)
- University of California, Irvine (US)
- Boston Children's Hospital (US)
- Hong Kong University of Science and Technology (HK)
- Corresponding author
- Baker, David
- ORCID
- Chevalier, Aaron
- Silva, Daniel-Adriano
- Hicks, Derrick R.
- Vergara, Renan
- Murapa, Patience
- Bernard, Steffen M.
- Zhang, Lu
- Lam, Kwok-Ho
- Yao, Guorui
- Bahl, Christopher D.
- Miyashita, Shin-Ichiro
- Goreshnik, Inna
- Fuller, James T.
- Jenkins, Cody M.
- Carter, Lauren
- Bryan, Cassie M.
- Stewart, Lance
- Dong, Min
- Huang, Xuhui
- Jin, Rongsheng
- Wilson, Ian A.
- Fuller, Deborah H.
- Baker, David
- Venue
- Nature
- Published
- 2017-09-27
- Volume
- 550
- Issue
- 7674
- Pages
- 74-79
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5802399
- OpenAlex
- W2759860792
- Cited by
- 453
- References
- 48
- Citations by year
- 2026: 28 · 2025: 57 · 2024: 48 · 2023: 42 · 2022: 59 · 2021: 55 · 2020: 57 · 2019: 53 · 2018: 48 · 2017: 6
- FWCI
- 18.31
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
- Funders
- National Institutes of Health (1s10od021527-01, 5t32ai007354-30)
- National Institute of General Medical Sciences (P41GM103403)
- National Institute of Allergy and Infectious Diseases (R41AI122431, R01AI091823, R56AI127371, R56AI117675, R21AI119258, R33AI119258, R21AI123920, T32-AI007354., R01AI125704)
- National Institute of Neurological Disorders and Stroke (R01NS080833)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Immunology and Microbiology › Immunology › Monoclonal and Polyclonal Antibodies Research
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Keywords
- de novo protein design, miniproteins, protein binders, influenza haemagglutinin, botulinum neurotoxin B, oligonucleotide synthesis, protein stability, antiviral agents, prophylactic protection, antibody alternatives, immune response
- MeSH terms
- Botulinum Toxins, Computer Simulation, Hot Temperature, Humans, Influenza, Human, Protein Binding, Proteins, Temperature, Drug Design, Protein Engineering, Hemagglutinin Glycoproteins, Influenza Virus, Protein Stability, Molecular Dynamics Simulation, Molecular Targeted Therapy
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