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

Area of Science:

• Medicinal Chemistry
• Computational Chemistry
• Biochemistry

Background:

• Cyclic peptides with intramolecular disulfide bonds are crucial in pharmaceuticals for treating cancer, autoimmune, and orphan diseases.
• The formation of these disulfide bonds is critical for peptide yield and purity, but the mechanism of iodine-mediated oxidation is not well understood.
• Current methods lack predictive models for optimizing disulfide bond formation.

Purpose of the Study:

• To elucidate the molecular mechanism of intramolecular disulfide bond formation in cyclic peptides via iodine-mediated oxidation.
• To develop a predictive kinetic model for optimizing the disulfide bond closure step.
• To provide insights into improving the synthesis of cyclic peptide therapeutics.

Main Methods:

• Utilized hybrid density functional theory (DFT) methods (PBE0-D3BJ/def2-TZVP/PCM(DMF)) to investigate the reaction mechanism.
• Established the intramolecular SN2-cyclization pathway and competing side reactions.
• Developed and validated a two-parameter kinetic model against experimental data.

Main Results:

• Identified a competing SN2-cyclization mechanism and a second cysteine oxidation pathway.
• Provided the first computational evidence for a diiodinated intermediate under excess iodine, which lowers cyclic disulfide yield.
• Developed a kinetic model that accurately predicts optimal iodine stoichiometry for various peptide structures.

Conclusions:

• The study clarifies the mechanism of iodine-mediated disulfide bond formation in cyclic peptides.
• The developed kinetic model enables prediction of optimal reaction conditions, enhancing synthesis efficiency.
• This work advances the development of cyclic peptide-based therapeutics by improving synthetic control.