Work

An Electrochemical Approach to Peptide Linker Synthesis for Drug Conjugate Development

Year: 2025

Type: preprint

Abstract: Drug conjugates are revolutionizing the pharmaceutical landscape by offering new opportunities for targeted interventions. As an integral component to conjugate design, the chemical linker—the region between drug payload and targeting vector—requires careful preclinical evaluation and optimization. In this study, we report the development of an electrochemical decarboxylation-transetherification methodology that facilitates efficient access to peptide-based N,O-acetal linkers, a valuable class of chemical spacer featured in an increasing number of clinically validated antibody-drug conjugates (ADCs). Beginning with a peptide C-terminal carboxylic acid, an anodic decarboxylation to forge a diversifiable peptide N,O- acetal intermediate is paired with development of a robust transetherification method—the scope of which is examined with the aid of high-throughput experimentation (HTE)—to install diverse, drug-like alcohol payloads onto the peptide chain. Salient features include the replacement of commonly employed, toxic chemical oxidants such as Pb(OAc)4 with an environmentally-benign electrochemical approach, and the ability to directly modify unprotected peptides, including substrates bearing valuable bioconjugation handles. The power of the method for ADC synthesis is exemplified by preparation of the linker construct featured in trastuzumab deruxtecan (Enhertu®), an approved cancer therapeutic.

Source: ChemRxiv

DOI: 10.26434/chemrxiv-2025-jl7g6