Conotoxins containing nonnatural backbone spacers: Cladistic-based design, chemical synthesis, and improved analgesic activity
- Author(s)
- Green, BR; Catlin, P; Zhang, MM; Fiedler, B; Bayudan, W; Morrison, A; Norton, RS; Smith, BJ; Yoshikami, D; Olivera, BM; Bulaj, G;
- Details
- Publication Year 2007-04,Volume 14,Issue #4,Page 399-407
- Journal Title
- CHEMISTRY & BIOLOGY
- Publication Type
- Journal Article
- Abstract
- Disulfide-rich neurotoxins from venomous animals continue to provide compounds with therapeutic potential. Minimizing neurotoxins often results in removal of disulfide bridges or critical amino acids. To address this drug-design challenge, we explored the concept of disulfide-rich scaffolds consisting of isostere polymers and peptidic pharmacophores. Flexible spacers, such as amino-3-oxapentanoic or 6-aminohexanoic acids, were used to replace conformationally constrained parts of a three-disulfide-bridged conotoxin, SIIIA. The peptide-polymer hybrids, polytides, were designed based on cladistic identification of nonconserved loci in related peptides. After oxidative folding, the polytides appeared to be better inhibitors of sodium currents in dorsal root ganglia and sciatic nerves in mice. Moreover, the polytides appeared to be significantly more potent and longer-lasting analgesics in the inflammatory pain model in mice, when compared to SIIIA. The resulting polytides provide a promising strategy for transforming disulfide-rich peptides into therapeutics.
- Publisher
- CELL PRESS
- Keywords
- RESISTANT SODIUM-CHANNELS; SHK TOXIN; PROTEIN PROSTHESIS; OMEGA-CONOTOXIN; PEPTIDE ANALOGS; III MIMETICS; CYCLIZATION; INHIBITOR; STABILITY; DISCOVERY
- Publisher's Version
- https://doi.org/10.1016/j.chembiol.2007.02.009
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2007-04-01 12:00:00