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Design of Bioactive Peptides from Naturally Occurring μ-Conotoxin Structures
- Source :
- Journal of Biological Chemistry. 287:31382-31392
- Publication Year :
- 2012
- Publisher :
- Elsevier BV, 2012.
-
Abstract
- To date, cone snail toxins ("conotoxins") are of great interest in the pursuit of novel subtype-selective modulators of voltage-gated sodium channels (Na(v)s). Na(v)s participate in a wide range of electrophysiological processes. Consequently, their malfunctioning has been associated with numerous diseases. The development of subtype-selective modulators of Na(v)s remains highly important in the treatment of such disorders. In current research, a series of novel, synthetic, and bioactive compounds were designed based on two naturally occurring μ-conotoxins that target Na(v)s. The initial designed peptide contains solely 13 amino acids and was therefore named "Mini peptide." It was derived from the μ-conotoxins KIIIA and BuIIIC. Based on this Mini peptide, 10 analogues were subsequently developed, comprising 12-16 amino acids with two disulfide bridges. Following appropriate folding and mass verification, blocking effects on Na(v)s were investigated. The most promising compound established an IC(50) of 34.1 ± 0.01 nm (R2-Midi on Na(v)1.2). An NMR structure of one of our most promising compounds was determined. Surprisingly, this structure does not reveal an α-helix. We prove that it is possible to design small peptides based on known pharmacophores of μ-conotoxins without losing their potency and selectivity. These data can provide crucial material for further development of conotoxin-based therapeutics. ispartof: Journal of Biological Chemistry vol:287 issue:37 pages:31382-31392 ispartof: location:United States status: published
- Subjects :
- Protein Folding
Stereochemistry
Peptide
Xenopus Proteins
Biology
complex mixtures
Biochemistry
Protein Structure, Secondary
Sodium Channels
Cone snail
Xenopus laevis
Animals
Conotoxin
Molecular Biology
Ion channel
chemistry.chemical_classification
Sodium channel
Cell Biology
Combinatorial chemistry
Peptide Conformation
Amino acid
chemistry
Protein Structure and Folding
Female
Pharmacophore
Conotoxins
Peptides
Ion Channel Gating
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 287
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....2addb0fbec2613f73dda5eff410a5094