Conotoxins containing nonnatural backbone spacers: cladistic-based design, chemical synthesis, and improved analgesic activity
| Autor: | Doju Yoshikami, Grzegorz Bulaj, Brian Fiedler, Baldomero M. Olivera, Brad R. Green, Raymond S. Norton, Alex Morrison, Brian J. Smith, Philip Catlin, Min Min Zhang, Wendi Bayudan |
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| Rok vydání: | 2006 |
| Předmět: |
Isostere
Stereochemistry Analgesic Clinical Biochemistry Molecular Sequence Data Pain Mice Inbred Strains Chemical synthesis Biochemistry Sodium current 03 medical and health sciences Mice Ganglia Spinal Drug Discovery Animals Conotoxin Amino Acid Sequence Molecular Biology 030304 developmental biology Pain Measurement chemistry.chemical_classification Pharmacology Neurons 0303 health sciences Chemistry Oxidative folding 030302 biochemistry & molecular biology General Medicine Analgesics Non-Narcotic Sciatic Nerve Amino acid Drug Design Molecular Medicine Pharmacophore Conotoxins Peptides Sodium Channel Blockers |
| Zdroj: | Chemistrybiology. 14(4) |
| ISSN: | 1074-5521 |
| Popis: | SummaryDisulfide-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. |
| Databáze: | OpenAIRE |
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