Conotoxins Targeting Neuronal Voltage-Gated Sodium Channel Subtypes: Potential Analgesics?

Abstract

Voltage-gated sodium channels (VGSC) are the primary mediators of electrical signal amplification and propagation in excitable cells. VGSC subtypes are diverse, with different biophysical and pharmacological properties, and varied tissue distribution. Altered VGSC expression and/or increased VGSC activity in sensory neurons is characteristic of inflammatory and neuropathic pain states. Therefore, VGSC modulators could be used in prospective analgesic compounds. VGSCs have specific binding sites for four conotoxin families: μ-, μO-, δ- and ί-conotoxins. Various studies have identified that the binding site of these peptide toxins is restricted to well-defined areas or domains. To date, only the μ- and μO-family exhibit analgesic properties in animal pain models. This review will focus on conotoxins from the μ- and μO-families that act on neuronal VGSCs. Examples of how these conotoxins target various pharmacologically important neuronal ion channels, as well as potential problems with the development of drugs from conotoxins, will be discussed.

Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels

“…Inhibition of Na v channel function via interaction with the voltage sensor region has previously been reported for spider (e.g., Protx II, HWTX-IV) and marine snail (MuO conotoxins) peptide toxins (16,(36)(37)(38), although much of the published data suggest that they primarily interact with the voltage sensor of homologous Domain 2 (16,17,(38)(39)(40). Several recent reports have also described possible interactions of Protx II with Domain 1, 3, and 4 voltage sensors (38)(39)(40).…”

Pharmacological characterization of conotoxin lt14a as a potent non-addictive analgesic

“…The traditional antinociceptive opioid drugs, such as morphine and pethidine, show a powerful antinociceptive efficacy; however, the development of tolerance and physical dependence is also a universal characteristic of these drugs (Chindo et al, 2009). As promising antinociceptive drugs, MVIIA, CVID, Vc1.2, m-and mO-conotoxins show efficient antinociceptive properties by targeting different molecular receptors (Indurthi et al, 2014b;Jayamanne et al, 2013;Klotz, 2006;Knapp et al, 2012;Wallace et al, 2008).…”

Structural basis of Nav1.7 inhibition by an isoform-selective small-molecule antagonist

“…Although block is state-dependent and generally thought to stabilize inactivated states of the channel (21-23), these inhibitors lack molecular selectivity among the Nav1.1-1.9 isoforms owing to the high sequence conservation found within the PM (3,4). Isoformselective peptide toxins that target the outer vestibule are known (24,25), but these inhibitors lack state dependence and are unsuitable for oral dosing. To date, efforts to identify drugs with higher therapeutic index that target a receptor site offering improved isoform selectivity have failed (26,27).…”