Disulfide-rich Cyclic Peptides

Among the variety of post-translational modifications (PTMs), the disulfide bond has gained considerable momentum in biological chemistry as it occurs instantaneously through oxidative folding in peptides, proteins, hormones, enzymes, growth factors, toxins, and immunoglobulins. But the use of disulfide-rich cyclic peptides is faced with some synthetic challenges, mainly associated with construction of the circular backbone and formation of the correct disulfides.

Fig.1 The structure of two disulfide-rich peptides: α-Defensin 6 and Chlorotoxin

Disulfide-rich cyclic peptides and their disulfide bonds often have the following advantages:

• Disulfide bond cyclization improves the potency, rigidity, target selectivity, and stability of proteases
• Disulfide bond stabilizes the secondary structure of peptides
• As a common structural motif in therapeutically active compounds and nonribosomal natural products, disulfides have important biological activities
• Disulfide-rich cyclic peptides have exciting potential as leads or frameworks in drug discovery

Cyclic peptide synthesis has proven to be useful for several applications:

• Structural studies of peptides
• Investigation of peptides and their biological function
• Enzyme function and kinetics

Synthesis strategy

Among 20 kinds of amino acids, cysteines greatly contribute to the stabilization of the conformation by forming covalent disulfide bonds. The artificial formation of disulfide bridges requires the proper management of cysteine residues, including first protecting and then later removing side groups and properly pairing the cysteine residues. Cysteine is the prevailing site for covalent PTM in peptides and proteins.

Fig. 2 The formation of disulfide bond (Olivier Cheneval et al, 2014)

Available Disulfide-rich Cyclic Peptides Synthesis Services

Creative Peptides provides multiple methods for synthesizing disulfide-rich cyclic peptides:
• Classical peptide synthesis (solution phase, solid phase, or native chemical ligation) followed by oxidation
> Intermolecular (two peptide molecules are linked via the disulfide bridge), resulting in either:
   homodimers (two identical peptides) or heterodimers (two different peptides).
> Intramolecular (cyclization within one peptide molecule)
• Ugi multicomponent reaction (U-MCR)
   We provide peptides with up to 4 disulfide bonds in one peptide. Contact us to discuss your project details.

Creative Peptides is specialized in the custom synthesis of disulfide-rich cyclic peptides, providing a confidential and efficient service at competitive prices. Every step of peptide synthesis is subject to Creative Peptides' stringent quality control. Typical delivery specifications include:
• HPLC chromatogram
• Mass spec analysis
• Synthesis report
• Certificate of Analyses

References
1. Cheneval, O., Schroeder, C. I., Durek, T., Walsh, P., Huang, Y. H., Liras, S., ... & Craik, D. J. (2014). Fmoc-based synthesis of disulfide-rich cyclic peptides. The Journal of organic chemistry, 79(12), 5538-5544.
2. Howl, J. (Ed.). (2005). Peptide synthesis and applications (Vol. 298). Springer Science & Business Media.
3. Vishwanatha, T. M., Bergamaschi, E., & Dömling, A. (2017). Sulfur-Switch Ugi Reaction for Macrocyclic Disulfide-Bridged Peptidomimetics. Organic letters, 19(12), 3195-3198.