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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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Self-citationDe novo protein fold design through sequence-independent fragment assembly simulations
Pearce, R., Huang, X., Omenn, G. S., & Zhang, Y. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2208275120 · Cited by 17
“For instance, approaches such as Rosetta have been applied to design proteins with promising therapeutic potential (9–11), novel ligand-binding activity (12, 13), and complex logical interactions (14).”
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Hecht, M. H., Zarzhitsky, S., Karas, C., & Chari, S. L. (2018) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2017.11.009 · Cited by 17
Fast and flexible design of novel proteins using graph neural networksPreprint
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Burnside, D. J., Schoenrock, A., Moteshareie, H., Hooshyar, M., Basra, P., Hajikarimlou, M., Dick, K., Barnes, B., Kazmirchuk, T. D. D., Jessulat, M., et al. (2018) · iScience · doi:10.1016/j.isci.2018.11.038 · Cited by 19
“Computational tools that can effectively design novel proteins specifically architected to interact with a wide range of targets are now beginning to emerge (Chevalier et al., 2017; Viart et al., 2016).”
BackgroundToward complete rational control over protein structure and function through computational design
Adolf‐Bryfogle, J., Teets, F. D., & Bahl, C. D. (2020) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2020.10.015 · Cited by 19
Self-citationA Deep SE(3)-Equivariant Model for Learning Inverse Protein FoldingPreprint
McPartlon, M., Lai, B., & Xu, J. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.04.15.488492 · Cited by 20
“Success in these areas has led to the development of enhanced therapeutics (Chevalier et al. 2017), biosensors (Quijano-Rubio et al. 2021), enzymes (Siegel et al. 2010) and more (Lucas and T. Kortemme 2020; Tinberg et al. 2013).”
BackgroundQuantifying Plant Biology with Fluorescent Biosensors
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Functionalized Protein Binders in Developmental Biology
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Self-citationDrugs, host proteins and viral proteins: how their promiscuities shape antiviral design
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“Chevalier et al. (2017) used their Rosetta program to design and screen peptides of about 40 amino acids for selected targets.”
MethodHomology Molecular Modeling - Perspectives and Applications
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“The Kd values were estimated by plotting absorbance at λmax (414 nm) versus heme concentration using the equation (1) for high-affinity heme binding.”
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“However,these techniques are often difficult and time consuming (Nanev 2020) spurring the development of the in silico methods to accomplish a variety of tasks involving protein structure (Vakser 2014, Sesterhenn et al. 2020, Chevalier et al. 2017, Maia et al. 2020).”
Modeling and Predicting the Activities of Trans-Acting Splicing Factors with Machine Learning
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“They also de novo designed RBD-binding proteins by using rotamer interaction field docking [74] with large in silico mini-protein libraries [75], followed by the design to generate binders to the distinct regions of the RBD surface [70], the sequences of peptides designed are shown in Table 1…”
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Self-citationStructures and disulfide cross‐linking of de novo designed therapeutic mini‐proteins
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Self-citationStructural Insights for Anti-Influenza Vaccine Design
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De Novo Protein Design Using the Blueprint Builder in Rosetta
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Randomized gates eliminate bias in sort‐seq assays
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Self-citationDe novo design of mini-binder proteins against IL-2 receptor β chain
Ming, K., Xing, B., Ren, X., Hu, Y., Wei, L., Wang, Z., Mei, M., Weng, J., & Wei, Z. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.133834 · Cited by 11
De Novo Design of Proteins for Autocatalytic Isopeptide Bond Formation
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“One key advantage of de novo scaffolds is that they are often exceptionally stable [25] and, hence, tolerate the incorporation of functional sites that typically are destabilizing to proteins.”
BackgroundInfluentialIntelligent Protein Design and Molecular Characterization Techniques: A Comprehensive Review
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Identifying well-folded de novo proteins in the new era of accurate structure prediction
Peñas-Utrilla, D., & Marcos, E. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.991380 · Cited by 6
“First, a dataset of miniprotein binders designed to bind the Botulinum neurotoxin B (BoNT/B) (Chevalier et al., 2017) (“BoNT dataset”).”
BackgroundArtificial Intelligence: A New Tool for Structure-Based G Protein-Coupled Receptor Drug Discovery
Chung, J., Hahn, H., Flores-Espinoza, E., & Thomsen, A. R. B. (2025) · Biomolecules · doi:10.3390/biom15030423 · Cited by 9
“…to being important for understanding their function in biological processes, protein 3D structures provide critical insights into the potential for designing compounds that can bind to and modulate their function, thus offering a way to regulate entire biological pathways and processes [2,3].”
Novack, D., Raddi, R. M., Zhang, S., Hurley, M. F. D., & Voelz, V. A. (2025) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.5c00704 · Cited by 10
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Selection pressures on evolution of ribonuclease H explored with rigorous free–energy–based design
Hayes, R. L., Nixon, C. F., Marqusee, S., & Brooks, C. L. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2312029121 · Cited by 8
Role of Force Fields in Protein Function Prediction
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“The recent study by David Baker’s group creates a platform for the design, testing, and refinement of small therapeutic proteins (Chevalier et al., 2017) and uses this to create de novo designed protein inhibitors of influenza and botulinum toxin.”
BackgroundCreation of artificial protein–protein interactions using α-helices as interfaces
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De novo design of modular and tunable allosteric biosensorsPreprint
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Self-citationDesign of High Affinity Binders to Convex Protein Target SitesPreprint
Baker, D. A., Yang, W., Hicks, D. R., Ghosh, A., Schwartze, T. A., Coventry, B., Goreshnik, I., Allen, A., Halabiya, S. F., Kim, C., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.01.592114 · Cited by 11
“We used the RIF based docking protocol of Cao et al 3 to dock both the 5HCS scaffolds described above and the globular miniprotein scaffold library used in the previous studies 2,12 to the TGF-β binding site 13 (Fig.”
Self-citationIn vivo selection of synthetic nucleocapsids for tissue targeting
Olshefsky, A., Benasutti, H., Sylvestre, M., Butterfield, G. L., Rocklin, G. J., Richardson, C., Hicks, D. R., Lajoie, M. J., Song, K., Leaf, E. M., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2306129120 · Cited by 8
“For our purposes, we viewed these miniproteins as simply small, stable domains with surface patches that have physicochemical properties typical of protein - protein interfaces (20, 21).”
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Self-citationMain methods and tools for peptide development based on protein-protein interactions (PPIs)
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Grafted Coiled-Coil Peptides as Multivalent Scaffolds for Protein Recognition
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Key aspects of the past 30 years of protein design
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“The FastDesign method found many applications for the design of new protein functions [14, 129, 130].”
Mapping functional regions of essential bacterial proteins with dominant-negative protein fragments
Savinov, A., Fernandez, A., & Fields, S. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2200124119 · Cited by 8
“Synthetic peptides can also be engineered for such inhibitory functions, providing potential avenues for novel cancer therapeutics (8), antivirals (9) and antibiotics (10).”
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Net Charge and Nonpolar Content Guide the Identification of Folded and Prion Proteins
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RosettaSurf—A surface-centric computational design approach
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Derivative free optimization via repeated classificationPreprint
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“More concretely, consider the optimization of protein binding affinity to DNA sequence targets from biosensor data [11, 21, 38].”
BackgroundSelf-assembled proteomimetic (SAP) with antibody-like binding from short PNA–peptide conjugates
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“In parallel, Baker and coworkers have leveraged advances in the computational approach to identify de novo miniproteins with exceptionally high affinity for select targets ( 27 , 28 ).”
Harnessing Deep Learning Methods for Voltage-Gated Ion Channel Drug Discovery
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Engineering of protein crystals for development of bionanomaterials
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Miniprotein-Based Artificial Retroaldolase
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Selection and evolution of disulfide-rich peptides via cellular protein quality control
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Biomolecular Structures: Prediction, Identification and Analyses
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De novo protein design enables precise induction of functional antibodies in vivoPreprint
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“Recently, Correia and colleagues (12) have shown that computationally designed immunogens could elicit epitope-specific responses.”
InfluentialDesigned Endocytosis-Triggering Proteins mediate Targeted DegradationPreprint
Huang, B., Abedi, M. H., Ahn, G., Coventry, B., Sappington, I., Wang, R., Schlichthaerle, T., Zhang, J. Z., Wang, Y., Goreshnik, I., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.19.553321 · Cited by 7
“De novo protein design has the advantage of being able to target binders to specific sites of interest on a target 13–15 , and thus is well suited to designing protein binders that target receptor sites that do not overlap with those of native ligands.”
BackgroundMethodSelf-citationLiu, Z., Yang, Y. L., Chen, M., Chen, X., Ming, K., Liu, Y., Weng, J., Xing, B., Wei, L., Wang, Z., et al. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.142293 · Cited by 5
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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