Paired-Fraction Electrochemical Programming for Somatostatin-14 Manufacture: Disulfide Closure under a Tryptophan-Oxidation Constraint

Somatostatin-14 is a 14-residue cyclic peptide closed by a Cys3-Cys14 disulfide and containing an oxidation-sensitive Trp8 residue. This combination makes it a discriminating test of paired-fraction electrochemical programming (PFEP): a useful process must create the disulfide without converting nonspecific oxidative capacity into tryptophan damage, intermolecular disulfides, or aggregation. The proposed method uses a divided cell to generate anodic and cathodic fractions outside the peptide reactor, releases each fraction against chemical specifications, and meters state dose under LC-MS and free-thiol feedback. The central prediction is not that electrochemical origin confers intrinsic selectivity. It is that small, time-resolved capacity increments, combined with a defined thiol-disulfide mediator and an early stopping rule, can reduce residence time outside the productive redox window. A staged experimental programme is described, including conventional SPPS, fraction qualification, low-concentration cyclization, Trp-specific impurity tracking, disulfide confirmation, functional testing, and chemically reconstructed controls. The hypothesis fails if equivalent pH and reactive-species trajectories reproduce the result or if Trp oxidation rises without improved isolated yield. No experimental performance or drug-product stability claim is made. Article type: Perspective, mechanistic hypothesis, and experimental framework. No experimental peptide yield, potency, clinical effect, or shelf-life evidence is reported.