Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines
Abstract The covalent attachment of peptide antigens to the NKT cell agonist, α‐galactosylceramide (αGalCer), generates self‐adjuvanting vaccines that prevent and/or eliminate disease in animal models of cancer and infectious disease. To date, the manufacture of these glycolipid‐peptide (GLP) conjug...
Saved in:
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley-VCH
2025-01-01
|
| Series: | ChemistryEurope |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/ceur.202400059 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1841543729894129664 |
|---|---|
| author | Dr. Michael A. Meijlink Dr. Susanna T. S. Chan Kathryn J. Farrand Sarah L. Draper Dr. Oliva K. Burn Jasmine M. Seifert‐Simpson Ngarangi C. Mason Dr. Lisa M. Connor Prof. Ian F. Hermans Prof. Gavin F. Painter Dr. Benjamin J. Compton |
| author_facet | Dr. Michael A. Meijlink Dr. Susanna T. S. Chan Kathryn J. Farrand Sarah L. Draper Dr. Oliva K. Burn Jasmine M. Seifert‐Simpson Ngarangi C. Mason Dr. Lisa M. Connor Prof. Ian F. Hermans Prof. Gavin F. Painter Dr. Benjamin J. Compton |
| author_sort | Dr. Michael A. Meijlink |
| collection | DOAJ |
| description | Abstract The covalent attachment of peptide antigens to the NKT cell agonist, α‐galactosylceramide (αGalCer), generates self‐adjuvanting vaccines that prevent and/or eliminate disease in animal models of cancer and infectious disease. To date, the manufacture of these glycolipid‐peptide (GLP) conjugate vaccines utilises an automated solid‐phase process to produce the peptide followed by a manual ‘wet chemistry’ conjugation step. To expedite GLP vaccine manufacture, we sought to develop methodology that enables the attachment of resin‐bound peptide antigen to αGalCer via an amide bond thereby avoiding the need to carry out a separate chemoselective conjugation step. To facilitate this approach, novel analogues of αGalCer incorporating an activated ester spaced by an acid‐resistant, protease‐sensitive linker from either the 6′′‐position or the N‐acyl lipid were synthesised. Reacting these with resin‐bound peptide afforded the conjugate vaccines in good to excellent yields and purity. In vivo testing showed that vaccines incorporating peptide antigen attached via the galactosyl head group induced strong antigen specific CD8+ T cell responses compared to those with antigen attached via the lipid tail and control vaccine manufactured in a stepwise manner. |
| format | Article |
| id | doaj-art-f450b75990f344f0b9f065af9bca1d6b |
| institution | Kabale University |
| issn | 2751-4765 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley-VCH |
| record_format | Article |
| series | ChemistryEurope |
| spelling | doaj-art-f450b75990f344f0b9f065af9bca1d6b2025-01-13T07:31:32ZengWiley-VCHChemistryEurope2751-47652025-01-0131n/an/a10.1002/ceur.202400059Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate VaccinesDr. Michael A. Meijlink0Dr. Susanna T. S. Chan1Kathryn J. Farrand2Sarah L. Draper3Dr. Oliva K. Burn4Jasmine M. Seifert‐Simpson5Ngarangi C. Mason6Dr. Lisa M. Connor7Prof. Ian F. Hermans8Prof. Gavin F. Painter9Dr. Benjamin J. Compton10Ferrier Research Institute Victoria University of Wellington 5010 Lower Hutt New ZealandFerrier Research Institute Victoria University of Wellington 5010 Lower Hutt New ZealandMalaghan Institute of Medical Research 6012 Wellington New ZealandFerrier Research Institute Victoria University of Wellington 5010 Lower Hutt New ZealandMalaghan Institute of Medical Research 6012 Wellington New ZealandFerrier Research Institute Victoria University of Wellington 5010 Lower Hutt New ZealandMalaghan Institute of Medical Research 6012 Wellington New ZealandMalaghan Institute of Medical Research 6012 Wellington New ZealandMalaghan Institute of Medical Research 6012 Wellington New ZealandFerrier Research Institute Victoria University of Wellington 5010 Lower Hutt New ZealandFerrier Research Institute Victoria University of Wellington 5010 Lower Hutt New ZealandAbstract The covalent attachment of peptide antigens to the NKT cell agonist, α‐galactosylceramide (αGalCer), generates self‐adjuvanting vaccines that prevent and/or eliminate disease in animal models of cancer and infectious disease. To date, the manufacture of these glycolipid‐peptide (GLP) conjugate vaccines utilises an automated solid‐phase process to produce the peptide followed by a manual ‘wet chemistry’ conjugation step. To expedite GLP vaccine manufacture, we sought to develop methodology that enables the attachment of resin‐bound peptide antigen to αGalCer via an amide bond thereby avoiding the need to carry out a separate chemoselective conjugation step. To facilitate this approach, novel analogues of αGalCer incorporating an activated ester spaced by an acid‐resistant, protease‐sensitive linker from either the 6′′‐position or the N‐acyl lipid were synthesised. Reacting these with resin‐bound peptide afforded the conjugate vaccines in good to excellent yields and purity. In vivo testing showed that vaccines incorporating peptide antigen attached via the galactosyl head group induced strong antigen specific CD8+ T cell responses compared to those with antigen attached via the lipid tail and control vaccine manufactured in a stepwise manner.https://doi.org/10.1002/ceur.202400059glycolipid-peptide conjugateα-galactosylceramidesolid-phase vaccine synthesiscytotoxic T lymphocytes |
| spellingShingle | Dr. Michael A. Meijlink Dr. Susanna T. S. Chan Kathryn J. Farrand Sarah L. Draper Dr. Oliva K. Burn Jasmine M. Seifert‐Simpson Ngarangi C. Mason Dr. Lisa M. Connor Prof. Ian F. Hermans Prof. Gavin F. Painter Dr. Benjamin J. Compton Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines ChemistryEurope glycolipid-peptide conjugate α-galactosylceramide solid-phase vaccine synthesis cytotoxic T lymphocytes |
| title | Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines |
| title_full | Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines |
| title_fullStr | Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines |
| title_full_unstemmed | Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines |
| title_short | Developing an On‐Resin Synthesis of α‐Galactosylceramide‐Peptide Conjugate Vaccines |
| title_sort | developing an on resin synthesis of α galactosylceramide peptide conjugate vaccines |
| topic | glycolipid-peptide conjugate α-galactosylceramide solid-phase vaccine synthesis cytotoxic T lymphocytes |
| url | https://doi.org/10.1002/ceur.202400059 |
| work_keys_str_mv | AT drmichaelameijlink developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT drsusannatschan developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT kathrynjfarrand developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT sarahldraper developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT drolivakburn developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT jasminemseifertsimpson developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT ngarangicmason developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT drlisamconnor developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT profianfhermans developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT profgavinfpainter developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines AT drbenjaminjcompton developinganonresinsynthesisofagalactosylceramidepeptideconjugatevaccines |