Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Solid-Phase Synthesis of Octapeptin Lipopeptides

  • Protocol
  • First Online:
Peptide Synthesis

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2103))

Abstract

Octapeptins are naturally derived cyclic lipopeptide antibiotics with activity against a range of Gram-negative pathogens, including highly resistant strains. Octapeptin C4, an exemplar of the class, was synthesized using a combination of Fmoc solid-phase peptide synthesis (SPPS) and solution-phase cyclization. Utilizing H-l-Leu-2-chlorotrityl resin, peptide couplings were performed using HCTU and collidine in DMF. The linear sequence was terminated by N-acylation with 3-(R)-hydroxydecanoic acid. The residue Dab-2 was orthogonally protected with 1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)isovaleryl group (ivDde) to enable selective side-chain deprotection prior to resin cleavage. Resin cleavage was accomplished with hexafluoroisopropanol in DCM, followed by cyclization with diphenylphosphoryl azide (DPPA) and solid sodium bicarbonate in DMF.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 149.00
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Poirel L, Jayol A, Nordmann P (2017) Polymyxins: antibacterial activity, susceptibility testing, and resistance mechanisms encoded by plasmids or chromosomes. Clin Microbiol Rev 30(2):557–596. https://doi.org/10.1128/CMR.00064-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wang R, van Dorp L, Shaw LP et al (2018) The global distribution and spread of the mobilized colistin resistance gene mcr-1. Nat Commun 9(1):1179. https://doi.org/10.1038/s41467-018-03205-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Butler MS, Blaskovich MAT, Cooper MA (2017) Antibiotics in the clinical pipeline at the end of 2015. J Antibiot 70(1):3–24. https://doi.org/10.1038/ja.2016.72

    Article  CAS  PubMed  Google Scholar 

  4. Blaskovich MAT, Pitt ME, Elliott AG et al (2018) Can octapeptin antibiotics combat extensively drug-resistant (XDR) bacteria? Expert Rev Anti Infect Ther 16(6):485–499. https://doi.org/10.1080/14787210.2018.1483240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Becker B, Butler MS, Hansford KA et al (2017) Synthesis of octapeptin C4 and biological profiling against NDM-1 and polymyxin-resistant bacteria. Bioorg Med Chem Lett 27(11):2407–2409. https://doi.org/10.1016/j.bmcl.2017.04.027

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Velkov T, Gallardo-Godoy A, Swarbrick JD et al (2018) Structure, function, and biosynthetic origin of octapeptin antibiotics active against extensively drug-resistant Gram-negative bacteria. Cell Chem Biol 25(4):380–391. e385. https://doi.org/10.1016/j.chembiol.2018.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Magee TV, Brown MF, Starr JT et al (2013) Discovery of Dap-3 polymyxin analogues for the treatment of multidrug-resistant Gram-negative nosocomial infections. J Med Chem 56(12):5079–5093. https://doi.org/10.1021/jm400416u

    Article  CAS  PubMed  Google Scholar 

  8. Ramesh S, Govender T, Kruger HG et al (2016) An improved and efficient strategy for the total synthesis of a colistin-like peptide. Tetrahedron Lett 57(17):1885–1888. https://doi.org/10.1016/j.tetlet.2016.03.055

    Article  CAS  Google Scholar 

  9. Filler R, Schure RM (1967) Highly acidic perhalogenated alcohols. A new synthesis of perfluoro-t-butyl alcohol. J Org Chem 32(4):1217–1219. https://doi.org/10.1021/Jo01279a081

    Article  CAS  Google Scholar 

  10. Bollhagen R, Schmiedberger M, Barlos K et al (1994) A new reagent for the cleavage of fully protected peptides synthesized on 2-chlorotrityl chloride resin. J Chem Soc Chem Commun 1994(22):2559–2560. https://doi.org/10.1039/C39940002559

    Article  Google Scholar 

  11. De Zoysa GH, Cameron AJ, Hegde VV et al (2015) Antimicrobial peptides with potential for biofilm eradication: synthesis and structure activity relationship studies of battacin peptides. J Med Chem 58(2):625–639. https://doi.org/10.1021/jm501084q

    Article  CAS  PubMed  Google Scholar 

  12. Shioiri T, Yamada S, Ninomiya K (1972) Diphenylphosphoryl azide—new convenient reagent for a modified curtius reaction and for peptide synthesis. J Am Chem Soc 94(17):6203–6205. https://doi.org/10.1021/Ja00772a052

    Article  CAS  PubMed  Google Scholar 

  13. Thomas AV, Ghosh AK, Sridhar PR (2001) Diphenyl phosphorazidate. In: e-EROS: encyclopedia of reagents for organic synthesis. John Wiley & Sons, Inc., Hoboken, New Jersey. https://doi.org/10.1002/047084289X.rd434.pub2

    Chapter  Google Scholar 

  14. Brady SF, Freidinger RM, Paleveda WJ et al (1987) Large-scale synthesis of a cyclic hexapeptide analog of somatostatin. J Org Chem 52(5):764–769. https://doi.org/10.1021/Jo00381a011

    Article  CAS  Google Scholar 

  15. Pearson DA, Blanchette M, Baker ML et al (1989) Trialkylsilanes as scavengers for the trifluoroacetic-acid deblocking of protecting groups in peptide-synthesis. Tetrahedron Lett 30(21):2739–2742. https://doi.org/10.1016/S0040-4039(00)99113-5

    Article  CAS  Google Scholar 

  16. Novabiochem, Innovations 3/10. https://www.emdmillipore.com/Web-US-Site/en_CA/-/USD/ShowDocument-Pronet?id=201010.178. Accessed 8 Nov 2019

Download references

Author information

Authors and Affiliations

  1. Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD, Australia

    Karl A. Hansford, Zyta M. Ziora, Matthew A. Cooper & Mark A. T. Blaskovich

Authors
  1. Karl A. Hansford
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Zyta M. Ziora
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Matthew A. Cooper
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark A. T. Blaskovich
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karl A. Hansford .

Editor information

Editors and Affiliations

  1. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, Australia

    Waleed M. Hussein

  2. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, Australia

    Mariusz Skwarczynski

  3. School of Chemistry and Molecular Biosciences, The University of Queensland, St. Lucia, QLD, Australia

    Istvan Toth

Rights and permissions

Reprints and permissions

Copyright information

© 2020 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Hansford, K.A., Ziora, Z.M., Cooper, M.A., Blaskovich, M.A.T. (2020). Solid-Phase Synthesis of Octapeptin Lipopeptides. In: Hussein, W., Skwarczynski, M., Toth, I. (eds) Peptide Synthesis. Methods in Molecular Biology, vol 2103. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-0227-0_13

Download citation

  • DOI: https://doi.org/10.1007/978-1-0716-0227-0_13

  • Published:

  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-0226-3

  • Online ISBN: 978-1-0716-0227-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics

Search

Navigation