Abstract by Peter Hammer Guldager Egelund

Novel peptide therapeutics for treatment of human illness are increasingly consisting of larger peptides. Current peptide active pharmaceutical ingredients (APIs) rarely exceed 50 amino acid residues, making them accessible by solid-phase peptide synthesis (SPPS). However, APIs are likely to increase significantly in size and complexity in the future, therefore an alternative synthetic method for large-scale manufacture is required, due to the limitations of SPPS. Convergent synthesis, and especially native chemical ligation (NCL), can access these compounds, wherein two peptide fragments through the use of an aromatic thiol catalyst are ligated together to give a native amide bond. Unfortunately, this method is currently too immature for large-scale production due to a number of process caveats, however, by combination of NCL and flow chemistry, several of the caveats can potentially be mitigated or outright solved.

We envisioned using an immobilised catalyst, that would utilise the efficient mixing and reaction control afforded by flow chemistry, and would allow easy reuse of the catalyst, and remove the requirement of purification prior to post-ligation methodologies. demonstrate the compatibility with larger polypeptides, the parathyroid hormone, an 84 amino acid residue protein containing a sterically hindered valine junction, was synthesised, and isolated in a 42 % yield. This methodology serves as a proof-of-concept and with further development may result in a method suitable for later large-scale production of peptide therapeutics. The knowledge gained in this project forms the basis for further studies regarding solid support and linker design that will likely improve the methodology described in this PhD thesis making it suitable for large scale peptide manufacture.