µ-Conotoxins as Leads in the Development of New Analgesics

Abstract

Voltage-gated sodium channels (VGSCs) contain a specific binding site for a family of cone shell toxins known as µ-conotoxins. As some VGSCs are involved in pain perception and µ-conotoxins are able to block these channels, µ-conotoxins show considerable potential as analgesics. Recent studies have advanced our understanding of the three-dimensional structures and structure-function relationships of the µ-conotoxins, including their interaction with VGSCs. Truncated peptide analogues of the native toxins have been created in which secondary structure elements are stabilized by non-native linkers such as lactam bridges. Ultimately, it would be desirable to capture the favourable analgesic properties of the native toxins, in particular their potency and channel sub-type selectivity, in non-peptide mimetics. Such mimetics would constitute lead compounds in the development of new therapeutics for the treatment of pain.

Conotoxins: Review and Docking Studies to determine potentials of Conotoxin as an Anticancer Drug Molecule

“…Norton [48] reported Mu-conotoxins as leads in the development of new analgesics. Voltage-gated sodium channels (VGSCs) contain a specific binding site for a family of cone shell toxins known as mu-conotoxins.…”

“…In fact, recent studies have demonstrated that there are different families and super-families of conotoxins [43][44][45][46][47][48][49][50]; which may present different pharmacological activities. For instance, the group of Aguilar and Lopez-Vera, et al [43] studied some I-conotoxins in vermivorous species of the West Atlantic.…”

Molecular interaction of δ-conopeptide EVIA with voltage-gated Na+ channels

“…[18,20] The structure of δ-EVIA was earlier reported and shown to be characterized by a 1:1 cis/trans isomerism of the Leu 12 -Pro 13 peptide bond within loop 2 (residues [11][12][13][14][15][16][17][18][19] of the disulfide-bridged sequence. [21] Both isomers were separately analyzed (PDB ID: 1G1P and 1G1Z) and, in addition, the exclusive occurrence of a trans leucyl-proline bond was demonstrated for the P13A analog, which was also synthesized by the same group.…”

“…[11] This relatively simple interaction mechanism and the perspective to develop µ-conotoxins as drugs to suppress neuronal signaling and therefore to be applied as analgesics has fueled research in this direction. [12] Conotoxins of the O-superfamily also contain three disulfide bridges, but they are much more diverse. Besides the already mentioned -conotoxins, which target voltage-gated Ca 2+ channels, this superfamily comprises µO-and δ-conotoxins, both acting on Na V channels.…”

Voltage-gated sodium channels

“…Much effort has focused on modifying the 16-residue m-conotoxin KIIIA [71]. Wild-type m-conotoxin KIIIA is a potent blocker of Na V 1.2 with an IC 50 of 5 nM, which is 50-100-fold more potent than at Na V 1.7 [54,55].…”