Poster Presentation The 16th Australian Peptide Conference 2025

New Strategies for Electrochemical Peptide Modification (#229)

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

Electroorganic synthesis is gaining attention in peptide chemistry due to its applicability in high precision and programmable late-stage modifications.1 Sustainable and environmentally friendly protocols, including methods which reduce step counts and use mild reaction conditions, are appealing factors contributing to its widespread recognition.2 Here we describe examples of a few electrochemical peptide modifications developed in our laboratory that aim to further bridge the gap between electrochemistry and peptide chemistry.

By leveraging and building upon prior work on electrochemical decarboxylation chemistry3,4, we disclose a sustainable two-step anodic decarboxylation-transetherification5 pathway for synthesising the linker region of Enhertu®, a clinically-approved antibody drug conjugate (ADC)6. The electrochemical decarboxylation is highly desirable as an environmentally friendly approach that mitigates the use of toxic lead reagents involved in conventional synthetic approaches. Following decarboxylation, transesterification using diverse alcohols can then convert intermediate, electrochemically generated N,O-acetals into stable and high-value peptide N,O-acetals. The implementation of high-throughput experimentation (HTE) facilitated the construction of a library of N,O-acetals of varying complexity.5 Peptides bearing bioconjugation handles, such as azides, alkynes, and maleimides, as well as structures bearing a range of unprotected functionalities, were screened to elucidate the broader scope of viable peptide substrates. Additionally, the conjugation of a peptide N,O-acetal to exatecan6, has been demonstrated to affirm the practical impact of the methodology in ADC chemistry.5

Beyond anodic decarboxylation reactions, we investigate the electrochemical oxidation and reduction of peptides functionalised with hydrazide moieties. Motivated by the accessibility and popularity of hydrazides in the native chemical ligation (NCL)7 space, this synthetic handle is exploited herein as a multimodal source of high-value functional motifs via C-terminal and sidechain functionalisations.

 

1 Mackay, A. S.; Payne, R. J.; Malins, L. R. J. Am. Chem. Soc. 2022, 144, 23.

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

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

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

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