Delicate Balance of Intra- and Inter-Molecular Entropic Effects in S-S Peptide Cyclization

Cyclic peptides with intramolecular S-S bonds are an important segment of the pharmaceutical market and are actively investigated as drug candidates for cancer, orphan, and autoimmune diseases. The disulfide bond-forming step often dictates the yield and purity of these peptides, yet its molecular mechanism in iodine-mediated oxidation remains poorly understood, and no predictive model is available. Herein, we employ hybrid density functional theory methods (PBE0-D3BJ/def2-TZVP/PCM(DMF)) to establish the intramolecular SN2-cyclization mechanism and demonstrate that it closely competes with a second cysteine oxidation. We present the first computational evidence for a diiodinated intermediate formed under excess iodine conditions, which reduces cyclic disulfide yield by favoring the linear SH-peptide. Based on this mechanistic insight, we develop a two-parameter kinetic model predicting the optimal iodine stoichiometry for S-S bond closure in peptides of varying ring size and structure. The model shows excellent agreement with experimental data for three desamino analogues of neurohypophyseal hormones: atosiban, desmopressin, and desaminooxytocin.