Conotoxins Containing Nonnatural Backbone Spacers: Cladistic-Based Design, Chemical Synthesis, and Improved Analgesic Activity

Brad R. Green, Philip Catlin, Min Min Zhang, Brian Fiedler, Wendi Bayudan, Alex Morrison, Raymond S S. Norton, Brian J. Smith, Doju Yoshikami, Baldomero M. Olivera, Grzegorz Bulaj

Research output: Contribution to journalArticleResearchpeer-review

63 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)399-407
Number of pages9
JournalChemistry and Biology
Volume14
Issue number4
DOIs
Publication statusPublished - 20 Apr 2007
Externally publishedYes

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