Photochemically-enabled, post-translational production of C-terminal amides
Abstract C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here we report a straightforward and scalable approach to the C-terminal α-amidation of peptides and proteins from c...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-51005-5 |
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| author | David Hymel Felix Wojcik Kim S. Halskov Wouter F. J. Hogendorf Sydnee C. Wong Ben M. Williams Asmus R. Mortensen Nick Cox Ayesha Misquith Nanna B. Holländer Finn Matthiesen Suneet Mehrotra Michael R. Harris |
| author_facet | David Hymel Felix Wojcik Kim S. Halskov Wouter F. J. Hogendorf Sydnee C. Wong Ben M. Williams Asmus R. Mortensen Nick Cox Ayesha Misquith Nanna B. Holländer Finn Matthiesen Suneet Mehrotra Michael R. Harris |
| author_sort | David Hymel |
| collection | DOAJ |
| description | Abstract C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here we report a straightforward and scalable approach to the C-terminal α-amidation of peptides and proteins from cysteine-extended polypeptide precursors. This amidation protocol consists of three highly efficient steps: 1) selective cysteine thiol substitution with a photolabel, 2) photoinduced decarboxylative elimination and 3) enamide cleavage by simple acidolysis or inverse electron demand Diels-Alder reaction. We provide a blueprint for applying this protocol to the semi-recombinant production of therapeutically relevant targets where gram scale C-terminal α-amidation is achieved in a photoflow reactor on a recombinantly prepared peptide YY analogue and a GLP-1/amylin co-agonist precursor peptide. Robust performance of this reaction cascade in flow highlights the potential of this chemistry to enable amidated drug leads to enter development that would not be viable on commercial scale using existing technology. |
| format | Article |
| id | doaj-art-9979539e39a44b69b33db07562ed5803 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-9979539e39a44b69b33db07562ed58032024-12-01T12:34:52ZengNature PortfolioNature Communications2041-17232024-11-011511810.1038/s41467-024-51005-5Photochemically-enabled, post-translational production of C-terminal amidesDavid Hymel0Felix Wojcik1Kim S. Halskov2Wouter F. J. Hogendorf3Sydnee C. Wong4Ben M. Williams5Asmus R. Mortensen6Nick Cox7Ayesha Misquith8Nanna B. Holländer9Finn Matthiesen10Suneet Mehrotra11Michael R. Harris12Novo Nordisk Research Center Seattle, Inc.Research Chemistry, Novo Nordisk A/SResearch Chemistry, Novo Nordisk A/SResearch Chemistry, Novo Nordisk A/SNovo Nordisk Research Center Seattle, Inc.Chemical Development, Novo Nordisk A/SChemical Development, Novo Nordisk A/SNovo Nordisk Research Center Seattle, Inc.Novo Nordisk Research Center Seattle, Inc.Chemical Development, Novo Nordisk A/SPurification Technologies, Novo Nordisk A/SNovo Nordisk Research Center Seattle, Inc.Novo Nordisk Research Center Seattle, Inc.Abstract C-terminal α-amidated peptides are attractive therapeutic targets, but preparative methods to access amidated pharmaceuticals are limited both on lab and manufacturing-scale. Here we report a straightforward and scalable approach to the C-terminal α-amidation of peptides and proteins from cysteine-extended polypeptide precursors. This amidation protocol consists of three highly efficient steps: 1) selective cysteine thiol substitution with a photolabel, 2) photoinduced decarboxylative elimination and 3) enamide cleavage by simple acidolysis or inverse electron demand Diels-Alder reaction. We provide a blueprint for applying this protocol to the semi-recombinant production of therapeutically relevant targets where gram scale C-terminal α-amidation is achieved in a photoflow reactor on a recombinantly prepared peptide YY analogue and a GLP-1/amylin co-agonist precursor peptide. Robust performance of this reaction cascade in flow highlights the potential of this chemistry to enable amidated drug leads to enter development that would not be viable on commercial scale using existing technology.https://doi.org/10.1038/s41467-024-51005-5 |
| spellingShingle | David Hymel Felix Wojcik Kim S. Halskov Wouter F. J. Hogendorf Sydnee C. Wong Ben M. Williams Asmus R. Mortensen Nick Cox Ayesha Misquith Nanna B. Holländer Finn Matthiesen Suneet Mehrotra Michael R. Harris Photochemically-enabled, post-translational production of C-terminal amides Nature Communications |
| title | Photochemically-enabled, post-translational production of C-terminal amides |
| title_full | Photochemically-enabled, post-translational production of C-terminal amides |
| title_fullStr | Photochemically-enabled, post-translational production of C-terminal amides |
| title_full_unstemmed | Photochemically-enabled, post-translational production of C-terminal amides |
| title_short | Photochemically-enabled, post-translational production of C-terminal amides |
| title_sort | photochemically enabled post translational production of c terminal amides |
| url | https://doi.org/10.1038/s41467-024-51005-5 |
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