Structure and function of μ-conotoxins, peptide-based sodium channel blockers with analgesic activity

mu-Conotoxins block voltage-gated sodium channels (VGSCs) and compete with tetrodotoxin for binding to the sodium conductance pore. Early efforts identified mu-conotoxins that preferentially blocked the skeletal muscle subtype (Na(V)1.4). However, the last decade witnessed a significant increase in the number of mu-conotoxins and the range of VGSC subtypes inhibited (Na(V)1.2, Na(V)1.3 or Na(V)1.7). Twenty mu-conotoxin sequences have been identified to date and structure-activity relationship studies of several of these identified key residues responsible for interactions with VGSC subtypes. Efforts to engineer-in subtype specificity are driven by in vivo analgesic and neuromuscular blocking activities. This review summarizes structural and pharmacological studies of mu-conotoxins, which show promise for development of selective blockers of Na(V)1.2, and perhaps also Na(V)1.1,1.3 or 1.7.