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

Abstract

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.