Disulfide rich peptides exhibit exquisite stability due to the covalent stabilization of their secondary structure. After a particular sequence has been identified and mapped, these peptides are typically folded in solution under redox conditions, assuming that a single, thermodynamically stable conformation will be the predominant species. However, there have been several cases where multiple disulfide bonding patterns are observed upon folding completion in solution, demanding additional purification and significant characterization efforts before any biological assays can be performed.<br/>A simplified on-resin synthesis strategy is attractive as the purification and characterization steps can be minimized, if not completely eliminated, thereby increasing the overall yield of the peptide with the proper disulfide bond pattern. Herein we describe a fully automated, optimized solid phase synthesis of the cysteine-rich peptide linaclotide, a 14 amino acid peptide which is conformationally constrained by three disulfide bonds. Using Branches™, the synthesis and on-resin disulfide bond formation was readily visualized and programmed, simplifying the total synthesis ensuring that the proper disulfide bond pattern was achieved.

Disulfide rich peptides: Automating optimized syntheses and regioselective formation of disulfide bonds

2019 Spring National Meeting

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