Synthesis and activity of thioether-containing analogues of the complement inhibitor compstatin

Highlights:

• This study applies substitution of a disulfide bond with a reduction-resistant cystathionine bridge to the therapeutic complement inhibitor compstatin in an effort to maintain its potent activity while improving its biological stability.
• Thioether-containing compstatin analogues were produced via solid-phase peptide synthesis utilizing orthogonally protected cystathionine amino acid building blocks and solid-supported peptide cyclization.
• Overall, the affinity of these analogues for their biological target and potent inhibition of complement activation were largely maintained when compared to those of the parent disulfide-containing peptides.
• Conclusion: The improved stability to reduction conferred by the thioether bond makes this new class of compstatin peptides a promising alternative for therapeutic applications, and the versatility of this synthesis allows for exploration of disulfide-to-thioether substitution in a variety of other therapeutic peptides.