Synthesis of proteins by automated flow chemistry
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Abstract
Ribosomes can produce proteins in minutes and are largely constrained to proteinogenic amino acids. Here, we report highly efficient chemistry matched with an automated fast-flow instrument for the direct manufacturing of peptide chains up to 164 amino acids long over 327 consecutive reactions. The machine is rapid: Peptide chain elongation is complete in hours. We demonstrate the utility of this approach by the chemical synthesis of nine different protein chains that represent enzymes, structural units, and regulatory factors. After purification and folding, the synthetic materials display biophysical and enzymatic properties comparable to the biologically expressed proteins. High-fidelity automated flow chemistry is an alternative for producing single-domain proteins without the ribosome.
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Notorious challenges, including base-induced racemization of seco-acids containing an α-chirality center, Z/E isomerization of α,β-unsaturated seco-acids, and a competitive reaction involving intermolecular esterification leading to diolide side products, have rendered macrolactonization a formidable task.
“However, notorious challenges, including base-induced racemization of seco-acids containing an α-chirality center,47Z/E isomerization of α, β-unsaturated seco-acids,48 and a competitive reaction involving intermolecular esterification leading to the formation of diolide side products have rendered it a formidable task.”
From Ynamide Coupling Reagents: Origin and Advances (2024) · cites this paper as [48]
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- Authors
- Hartrampf, N., Saebi, A., Poskus, M., Gates, Z. P., Callahan, A. J., Cowfer, A. E., Hanna, S., Antilla, S., Schissel, C. K., Quartararo, A. J., Ye, X., Mijalis, A. J., Simon, M. D., Loas, A., Liu, S., Jessen, C., Nielsen, T. E., & Pentelute, B. L.
- Affiliations
- Massachusetts Institute of Technology (US)
- Novo Nordisk (Denmark) (DK)
- Corresponding author
- Saebi, A.
- Poskus, M.
- Pentelute, B. L.
- ORCID
- Venue
- Science
- Published
- 2020-05-29
- Volume
- 368
- Issue
- 6494
- Pages
- 980-987
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W3029756541
- Cited by
- 367
- References
- 72
- Citations by year
- 2026: 35 · 2025: 61 · 2024: 76 · 2023: 63 · 2022: 44 · 2021: 61 · 2020: 25
- FWCI
- 15.65
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- Science (publishedVersion)
- ChemRxiv (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Royal College of Surgeons in Ireland (submittedVersion, cc-by-nc-nd)
- Funders
- National Science Foundation (1122374)
- Novo Nordisk
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
- Physical Sciences › Engineering › Biomedical Engineering › Innovative Microfluidic and Catalytic Techniques Innovation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Keywords
- protein synthesis, translation elongation, single-domain proteins, protein folding, enzyme activity, protein purification
- MeSH terms
- Protein Domains, Peptides, Proteins, Protein Folding, Solid-Phase Synthesis Techniques
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