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

Abstract

Disulfide bonds are essential for the structural stability and biological activity of many bioactive peptides. However, these bonds are labile to reducing agents, which can limit the therapeutic utility of such peptides. Substitution of a disulfide bond with a reduction-resistant cystathionine bridge is an attractive means of improving stability while imposing minimal structural perturbation to the peptide. We have applied this approach to the therapeutic complement inhibitor compstatin, a disulfide-containing peptide currently in clinical trials for age-related macular degeneration, 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. Thus, the improved stability to reduction conferred by the thioether bond makes this new class of compstatin peptides a promising alternative for therapeutic applications. Additionally, the versatility of this synthesis allows for exploration of disulfide-to-thioether substitution in a variety of other therapeutic peptides.

• Authors: Patrick J Knerr, Apostolia Tzekou, Daniel Ricklin, Hongchang Qu, Hui Chen, Wilfred A van der Donk, John D Lambris
• Journal: ACS chemical biology (ACS Chem Biol) Vol. 6 Issue 7 Pg. 753-60 (Jul 15 2011) ISSN: 1554-8937 [Electronic] United States
• PMID: 21520911 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Complement C3
• Disulfides
• Peptides, Cyclic
• Sulfides
• compstatin

Topics

• Complement Activation (drug effects)
• Complement C3 (antagonists & inhibitors, metabolism)
• Disulfides (chemistry)
• Oxidation-Reduction
• Peptides, Cyclic (chemical synthesis, chemistry, pharmacology)
• Sulfides (chemistry)