Student or educator? Sign up with your school email and get 6 months of Pro free.
CoChat
Sign Up
Cited by 473

The DOI matches its Crossref record; 104 of the 104 references it cites were found in a registry or an index.

Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production

Open access
Isidro-Llobet, Albert, Kenworthy, Martin N., Mukherjee, Subha, Kopach, Michael E., Wegner, Katarzyna, Gallou, Fabrice, Smith, Austin G., Roschangar, Frank·2019·The Journal of Organic Chemistry
DOI 10.1021/acs.joc.8b03001
Open this paper in CoChat — free account

Abstract

In recent years, there has been a growing interest in therapeutic peptides within the pharmaceutical industry with more than 50 peptide drugs on the market, approximately 170 in clinical trials, and >200 in preclinical development. However, the current state of the art in peptide synthesis involves primarily legacy technologies with use of large amounts of highly hazardous reagents and solvents and little focus on green chemistry and engineering. In 2016, the ACS Green Chemistry Institute Pharmaceutical Roundtable identified development of greener processes for peptide API as a critical unmet need, and as a result, a new Roundtable team formed to address this important area. The initial focus of this new team is to highlight best practices in peptide synthesis and encourage much needed innovations. In this Perspective, we aim to summarize the current challenges of peptide synthesis and purification in terms of sustainability, highlight possible solutions, and encourage synergies between academia, the pharmaceutical industry, and contract research organizations/contract manufacturing organizations.

Overview

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1021/acs.joc.8b03001

Cites

104 of 104 references verified0 citation errors · 0 not checkable

Statistics

Verification

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Citations

Cites

Show all 104 references

Research works printed but not linked: 49

  1. https://www.acs.org/content/acs/en/greenchemistry/about.html (accessed March 15, 2019).
  2. Brown, 2015, Toward Sustainable Engineering Practices in Biologics Manufacturing
  3. Hruby, 1972, A New Machine for Automated Solid Phase Peptide Synthesis, Anal. Chem., 44, 343, 10.1021/ac60310a004 · doi:10.1021/ac60310a004
  4. Gausepohl, 1992, Automated multiple peptide synthesis, Pept. Res., 5, 315
  5. Bicciato, 1995, An Improved System for Automated Peptide Synthesis, Chem. Eng. Technol., 18, 210, 10.1002/ceat.270180310 · doi:10.1002/ceat.270180310
  6. Fields, 1993, Techniques in Protein Chemistry IV, 229, 10.1016/B978-0-12-058757-5.50030-5 · doi:10.1016/b978-0-12-058757-5.50030-5
  7. Ludwick, 1986, Association of Peptide Chains during Merrifield Solid-Phase Peptide Synthesis. A Deuterium NMR Study, J. Am. Chem. Soc., 108, 6493, 10.1021/ja00281a007 · doi:10.1021/ja00281a007
  8. Masuda, 2015, Microwave-assisted solid-phase peptide synthesis of neurosecretory protein GL composed of 80 amino acid residues, J. Pept. Sci., 21, 454, 10.1002/psc.2756 · doi:10.1002/psc.2756
  9. Mukherjee, 2016, Synthesis and Bioactivity of Diastereomers of the Virulence Lanthipeptide Cytolysin, Org. Lett., 18, 6188, 10.1021/acs.orglett.6b03246 · doi:10.1021/acs.orglett.6b03246
  10. Gnanaprakasam, 2011, Synthesis of amides from esters and amines with liberation of H2 under neutral conditions, J. Am. Chem. Soc., 133, 1682, 10.1021/ja109944n · doi:10.1021/ja109944n
  11. García-Martín, 2007, Chlorotrityl Chloride (CTC) Resin as a Reusable Carboxyl Protecting Group, QSAR Comb. Sci., 26, 1027, 10.1002/qsar.200720015 · doi:10.1002/qsar.200720015
  12. Harre, 1999, An efficient method for activation and recycling of trityl resins, React. Funct. Polym., 41, 111, 10.1016/S1381-5148(99)00039-5 · doi:10.1016/s1381-5148(99)00039-5
  13. Gentilucci, 2016, Modern tools for the chemical ligation and synthesis of modified peptides and proteins, Future Med. Chem., 8, 2287, 10.4155/fmc-2016-0175 · doi:10.4155/fmc-2016-0175
  14. Jin, 2017, Synthesis and structure-activity relationship of teixobactin analogues via convergent Ser ligation, Bioorg. Med. Chem., 25, 4990, 10.1016/j.bmc.2017.04.039 · doi:10.1016/j.bmc.2017.04.039
  15. Sugiyama, 2017, Synthesis of Tripeptides and Pentapeptides Using a Fluorous-Fmoc Protection Strategy, Synthesis, 49, 2187, 10.1055/s-0036-1588698 · doi:10.1055/s-0036-1588698
  16. van de Langemheen, 2014, Scaffolded multiple cyclic peptide libraries for protein mimics by native chemical ligation, Org. Biomol. Chem., 12, 4471, 10.1039/C4OB00190G · doi:10.1039/c4ob00190g
  17. Stoner, 1999, Synthesis of ABT-378, an HIV protease inhibitor candidate: Avoiding the use of carbodiimides in a difficult peptide coupling, Org. Process Res. Dev., 3, 145, 10.1021/op980214p · doi:10.1021/op980214p
  18. Ritter, 2017, Five green chemistry success stories, Chem. Eng. News, 95, 16
  19. Patel, 2017, Executive reveals how Amgen shifted to greener chemistry, Chem. Eng. News, 95, 27
  20. Roschangar, 2018, Inspiring process innovation: Via an improved green manufacturing metric: IGAL, Green Chem., 20, 2206, 10.1039/C8GC00616D · doi:10.1039/c8gc00616d
  21. Kelley, 1996, Therapeutic peptides: the devil is in the details the next generation of peptides pharmaceutical may push manufacturing processes beyond their limits, Nat. Biotechnol., 14, 28, 10.1038/nbt0196-28 · doi:10.1038/nbt0196-28
  22. Rodionov, 1992, A swellographic approach to monitoring continuous-flow solid-phase peptide synthesis, Pept. Res., 5, 119
  23. Caciagli, 1997, Large-scale production of peptides using the solid-phase continuous flow method. Preparative synthesis of the novel tachykinin antagonist MEN 10627, J. Pept. Sci., 3, 224, 10.1002/(SICI)1099-1387(199705)3:3<224::AID-PSC104>3.0.CO;2-Z · doi:10.1002/(sici)1099-1387(199705)3:3<224::aid-psc104>3.0.co;2-z
  24. Caciagli, 1998, Large-scale production of peptides using the solid phase continuous flow method. Part 2: preparative synthesis of a 26-mer peptide thrombin inhibitor, J. Pept. Sci., 4, 327, 10.1002/(SICI)1099-1387(199808)4:5<327::AID-PSC154>3.0.CO;2-Y · doi:10.1002/(sici)1099-1387(199808)4:5<327::aid-psc154>3.0.co;2-y
  25. Baxendale, 2006, A flow reactor process for the synthesis of peptides utilizing immobilized reagents, scavengers and catch and release protocols, Chem. Commun., 4835, 10.1039/b612197g · doi:10.1039/b612197g
  26. Jolley, 2017, Highly Productive Continuous Flow Synthesis of Di- and Tripeptides in Water, Org. Process Res. Dev., 21, 1557, 10.1021/acs.oprd.7b00214 · doi:10.1021/acs.oprd.7b00214
  27. Shemyakin, 1965, Synthesis of peptides in solution on a polymeric support I. Synthesis of glycylglycyl-l-leucylglycine, Tetrahedron Lett., 6, 2323, 10.1016/S0040-4039(00)70379-0 · doi:10.1016/s0040-4039(00)70379-0
  28. Bayer, 1972, Liquid Phase Synthesis of Peptides, Nature, 237, 512, 10.1038/237512a0 · doi:10.1038/237512a0
  29. Mutter, 1974, Rapid Procedure for Liquid-Phase Peptide Synthesis: The Crystallization Method, Angew. Chem., Int. Ed. Engl., 13, 88, 10.1002/anie.197400882 · doi:10.1002/anie.197400882
  30. Chiba, 2009, Synthesis of hydrophobic phase-tagged prolyl peptides featuring rapid reaction/separation, Tetrahedron, 65, 8014, 10.1016/j.tet.2009.07.045 · doi:10.1016/j.tet.2009.07.045
  31. Okada, 2015, Acid-Triggered Colorimetric Hydrophobic Benzyl Alcohols for Soluble Tag-Assisted Liquid-Phase Synthesis, Org. Lett., 17, 4264, 10.1021/acs.orglett.5b02057 · doi:10.1021/acs.orglett.5b02057
  32. Takahashi, 2012, Novel diphenylmethyl-Derived Amide Protecting Group for Efficient Liquid-Phase Peptide Synthesis: AJIPHASE, Org. Lett., 14, 4514, 10.1021/ol302002g · doi:10.1021/ol302002g
  33. Tamiaki, 2001, A Novel Protecting Group for Constructing Combinatorial Peptide Libraries, Bull. Chem. Soc. Jpn., 74, 733, 10.1246/bcsj.74.733 · doi:10.1246/bcsj.74.733
  34. Dang, 2015, Enhanced Solvation of Peptides Attached to “Solid-Phase” Resins: Straightforward Syntheses of the Elastin Sequence Pro-Gly-Val-Gly-Val-Pro-Gly-Val-Gly-Val, Org. Lett., 17, 3521, 10.1021/acs.orglett.5b01632 · doi:10.1021/acs.orglett.5b01632
  35. Seifert, 2016, GAP Peptide Synthesis via Design of New GAP Protecting Group: An Fmoc/tBu Synthesis of Thymopentin Free from Polymers, Chromatography and Recrystallization, Eur. J. Org. Chem., 2016, 1714, 10.1002/ejoc.201600026 · doi:10.1002/ejoc.201600026
  36. So, 2010, Organic Solvent Nanofiltration: A New Paradigm in Peptide Synthesis, Org. Process Res. Dev., 14, 1313, 10.1021/op1001403 · doi:10.1021/op1001403
  37. Chen, 2017, Implication of Side Reactions in Iterative Biopolymer Synthesis: The Case of Membrane Enhanced Peptide Synthesis, Ind. Eng. Chem. Res., 56, 6796, 10.1021/acs.iecr.7b01280 · doi:10.1021/acs.iecr.7b01280
  38. Schmidt, 2017, Enzyme-mediated ligation technologies for peptides and proteins, Curr. Opin. Chem. Biol., 38, 1, 10.1016/j.cbpa.2017.01.017 · doi:10.1016/j.cbpa.2017.01.017
  39. Yeboue, 2018, Metro T.-X., Peptide Couplings by Reactive Extrusion: Solid-Tolerant and Free from Carcinogenic, Mutagenic and Reprotoxic Chemicals, ACS Sustainable Chem. Eng., 6, 16001, 10.1021/acssuschemeng.8b04509 · doi:10.1021/acssuschemeng.8b04509
  40. Pratap Singh Jadaun, 2017, HPLC for Peptides and Proteins: Principles, Methods and Applications, Pharm. Methods, 8, 1
  41. Nogueira, 2005, Alternative high-performance liquid chromatographic peptide separation and purification concept using a new mixed-mode reversed-phase/weak anion-exchange type stationary phase, J. Chromatogr. A, 1089, 158, 10.1016/j.chroma.2005.06.093 · doi:10.1016/j.chroma.2005.06.093
  42. Müller-Späth, 2013, Enabling highpurities and yields in therapeutic peptide purification using multicolumn countercurrentsolvent gradient purification, Chim. Oggi-Chem. Today, 31, 56
  43. Shao, 2016, Rapid Separation of Five Cyclosporin Analogs by Supercritical Fluid Chromatography. Journal of Analytical Sciences, Methods and Instrumentation, J. Anal. Sci., Methods Instrum., 6, 23, 10.4236/jasmi.2016.62004 · doi:10.4236/jasmi.2016.62004
  44. Schneider, 1980, Liquid-liquid extraction in peptide synthesis, Int. J. Pept. Protein Res., 15, 411, 10.1111/j.1399-3011.1980.tb02916.x · doi:10.1111/j.1399-3011.1980.tb02916.x
  45. Cañete, 1988, Liquid-liquid extraction in continuous flow systems without phase separation, Anal. Chem., 60, 2354, 10.1021/ac00172a008 · doi:10.1021/ac00172a008
  46. Lee, 1997, Continuous extraction of penicillin G by an emulsion liquid membrane in a countercurrent extraction column, J. Membr. Sci., 124, 43, 10.1016/S0376-7388(96)00213-X · doi:10.1016/s0376-7388(96)00213-x
  47. Dehkordi, 2002, Application of a novel-opposed-jets contacting device in liquid–liquid extraction, Chem. Eng. Process., 41, 251, 10.1016/S0255-2701(01)00141-6 · doi:10.1016/s0255-2701(01)00141-6
  48. Schuur, 2011, Chiral separation by enantioselective liquid–liquid extraction, Org. Biomol. Chem., 9, 36, 10.1039/C0OB00610F · doi:10.1039/c0ob00610f
  49. Mant, 2007, Peptide Characterization and Application Protocols, 3

Cited by

See all 473

Metadata

Authors
Isidro-Llobet, A., Kenworthy, M. N., Mukherjee, S., Kopach, M. E., Wegner, K., Gallou, F., Smith, A. G., & Roschangar, F.
Venue
The Journal of Organic Chemistry
Publisher
American Chemical Society (ACS)
Published
2019-03-22
Volume
84
Issue
8
Pages
4615-4628
ISSN
  • 0022-3263 (ISSN-L)
  • 1520-6904
DOI
10.1021/acs.joc.8b03001
OpenAlex
W2926626251
Cited by
473
References
104
FWCI
13.75
Type
journal article
Language
en
Open access
hybrid
Licence
pubs.acs.org/page/policy/authorchoice_ccby_termsofuse.html (vor, 165 d)
Funders
American Chemical Society (NA)

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

How to cite

Cite CoChat for the checks on this page, and the paper for its own findings.

This page
CoChat. (2026). Citation check: Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production. https://app.cochat.ai/papers/10.1021/acs.joc.8b03001
The paper
Isidro-Llobet, A., Kenworthy, M. N., Mukherjee, S., Kopach, M. E., Wegner, K., Gallou, F., Smith, A. G., & Roschangar, F. (2019). Sustainability Challenges in Peptide Synthesis and Purification: From R&D to Production. The Journal of Organic Chemistry. https://doi.org/10.1021/acs.joc.8b03001

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.