Paired-Fraction Electrochemical Programming of Artificial Cysteine-Containing Cyclic Peptides: A Platform Theory across Disulfide, Thioether, and Ligation-Defined Macrocycles

Artificial cysteine-containing cyclic peptides span several chemistries that should not be collapsed into a single “electrochemical cyclization” claim. A Cys pair may close by disulfide oxidation; an N-terminal Cys may drive native chemical ligation to a backbone amide; cysteine thiol may react with a bifunctional electrophile to form thioether macrocycles; and multi-Cys sequences may require directed oxidative folding. This Perspective develops a platform extension of paired-fraction electrochemical programming (PFEP) for these distinct routes. PFEP is defined as ex situ generation, qualification, and time-resolved delivery of complementary anodic and cathodic chemical capacities to an electrode-free reaction. The theory predicts the greatest value when a synthesis requires temporally opposed states—for example, reduced thiol during ligation followed by oxidation during disulfide locking, or oxidative closure followed by reductive rescue of mispaired intermediates. A route-selection hierarchy, state-vector description, control structure, analytical package, and falsification criteria are proposed. The framework explicitly excludes reagent-free peptide-bond formation, universal sequence transfer, and ORP-only control. Multi-disulfide products require connectivity mapping and function; mass loss of 2 Da per disulfide is insufficient. This is a research programme, not evidence that any designed cyclic peptide has been manufactured successfully. Article type: Perspective, mechanistic hypothesis, and experimental framework. No experimental peptide yield, potency, clinical effect, or shelf-life evidence is reported.