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

  • 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.
Author and source information

Authors: Knerr PJ, Tzekou A, Ricklin D, Qu H, Chen H, van der Donk WA, Lambris JD.
Reference: ACS Chem Biol. 2011 Jul 15;6(7):753-60. doi: 10.1021/cb2000378. Epub 2011 May 23.