title: Design of bioactive peptides from naturally occurring μ-conotoxin structures.
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.
authors: Laboratory of Toxicology, Katholieke Universiteit (KU) Leuven, Campus Gasthuisberg O and N2, Herestraat 49 Box 922, 3000 Leuven, Belgium.
authors: Marijke
authors: M
authors: Stevens
authors: Steve
authors: S
authors: Peigneur
authors: Natalia
authors: N
authors: Dyubankova
authors: Eveline
authors: E
authors: Lescrinier
authors: Piet
authors: P
authors: Herdewijn
authors: Jan
authors: J
authors: Tytgat
mesh_terms: D000818:Animals; D020916:Conotoxins / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D015640:Ion Channel Gating / Q000187:drug effects*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D015222:Sodium Channels / Q000737:chemistry / Q000378:metabolism*; D029867:Xenopus Proteins / Q000737:chemistry / Q000378:metabolism*; D014982:Xenopus laevis
chemical_list: D020916:Conotoxins; D010455:Peptides; D015222:Sodium Channels; D029867:Xenopus Proteins; C036155:conotoxin MI