2lu6

Publication Abstract from PubMed

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 mu-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 mu-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 alpha-helix. We prove that it is possible to design small peptides based on known pharmacophores of mu-conotoxins without losing their potency and selectivity. These data can provide crucial material for further development of conotoxin-based therapeutics.

Design of bioactive peptides from naturally occurring mu-conotoxin structures.,Stevens M, Peigneur S, Dyubankova N, Lescrinier E, Herdewijn P, Tytgat J J Biol Chem. 2012 Sep 7;287(37):31382-92. doi: 10.1074/jbc.M112.375733. Epub 2012, Jul 6. PMID:22773842^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.