Poster Presentation 10th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2025

Electrochemically Enabled Peptide Late-Stage Modifications (129071)

Dhanya Karipal Padinjare Veedu 1 2 , Yutong Lin 1 2 , Alexandra Du 3 , Sijie Chen 3 , Meghan Baker 3 , Lara Malins 1 2
  1. Research School of Chemistry, Australian National University, Canberra, ACT, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT, Australia.
  3. Department of Discovery Chemistry, Merck & Co., Rahaway, NJ, USA

Electrosynthesis is a re-emerging and sustainable synthetic technique in organic chemistry that allows precision and programmable synthesis under mild reaction conditions.1,2 In our research, we disclose the electrochemical decarboxylation3-6 ̶ transetherification of peptides for the applications in the synthesis of Antibody Drug Conjugates (ADCs). This method enables the sustainable synthesis of peptide C-terminal N,O-acetals, which are used as cleavable linkers in ADCs.7 We demonstrate the synthesis of the Enhertu® linker8, which consists of Gly-Gly-Phe-Gly with a C-terminal N,O-acetal, using the developed two-step methodology. The electrochemical method mitigates the use of toxic lead reagents during the decarboxylation step, and this two-step approach eliminates the need for a multi-step solution-phase synthesis as opposed to the prior methods.9 Moreover, the transetherification step, using a high-throughput experimentation setup in collaboration with Merck, showcases the broader scope of the developed method.
In addition to anodic decarboxylation chemistry, we investigate the electrochemical oxidations and reductions of peptide hydrazides10 for C-terminal , as well as sidechain functionalisation strategies to access a library of high value peptide structures

References

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2 Yan, M.; Kawamata, Y.; Baran, P. S. Chem. Rev. 2017, 117, 13230–13319.

3 Lin, Y.; Malins, L. R. Chem. Sci. 2020, 11, 10752–10758.

4 Lin, Y.; Malins, L. R. J. Am. Chem. Soc. 2021, 143, 11811–11819.

5 Lin, Y.; Malins, L. R. Synthesis 2022, 54, 3558–356.

6 Renaud, P.; Seebach, D. Angew. Chem. Int. Ed. 1986, 25, 843.

7 Lin, Y.; Karipal Padinjare Veedu, D.; Du, A.; Chen, S. J.; Baker, M.; Malins, L. R. manuscript in preparation.

8 Dumontet, C; Reichert, J. M.; Senter, P. D.; Lambert, J. M.; Beck, A. Nat. Rev. Drug Discov. 2023, 22, 641­–661.

9 Vrljic, M.; Strop, P; Wong, J. C.; Pons, J. WO 2022/236136 Al, 2022.

10 Conibear, A. C.; Watson, E. E.; Payne, R. J.; Becker, C. F. W. Chem. Soc. Rev., 2018, 47, 9046.