Druggability of Voltage-Gated Sodium Channels—Exploring Old and New Drug Receptor Sites

Abstract

Voltage-gated ion channels are important drug targets because they play crucial physiological roles in both excitable and non-excitable cells. About 15% of clinical drugs used for treating human diseases target ion channels. However, most of these drugs do not provide sufficient specificity to a single subtype of the channels and their off-target side effects can be serious and sometimes fatal. Recent advancements in imaging techniques have enabled us for the first time to visualize unique and hidden parts of voltage-gated sodium channels in different structural conformations, and to develop drugs that further target a selected functional state in each channel subtype with the potential for high precision and low toxicity. In this review we describe the druggability of voltage-gated sodium channels in distinct functional states, which could potentially be used to selectively target the channels. We review classical drug receptors in the channels that have recently been structurally characterized by cryo-electron microscopy with natural neurotoxins and clinical drugs. We further examine recent drug discoveries for voltage-gated sodium channels and discuss opportunities to use distinct, state-dependent receptor sites in the voltage sensors as unique drug targets. Finally, we explore potential new receptor sites that are currently unknown for sodium channels but may be valuable for future drug discovery. The advancement presented here will help pave the way for drug development that selectively targets voltage-gated sodium channels.

Inhibition of Voltage-Gated Na+ Currents Exerted by KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea), an Inhibitor of Na+-Ca2+ Exchanging Process

“…Pertinent to this reaction scheme is thus that the open-blocked Na V channels tend to be not closed unless the KB-R7943 molecule dissociates from the binding site(s). Meanwhile, the time-dependent block caused by this compound suggests that it preferentially binds to and blocks the open/inactivated state (conformation) of the Na V channels, thereby leading to a destabilization in open conformation [ 16 ]. Moreover, although the steady-state I-V relationship of I Na(T) was unaffected during the presence of KB-R7943, this compound diminished the strength of I Na(W) or I Na(R) evoked by respective ascending or descending V ramp .…”

“…Moreover, in cultured hippocampal neurons, KB-R7943 exhibits neuroprotection from glutamate-induced excitotoxicity by blocking NMDA receptor-mediated activity (IC 50 = 13.4 μM) as well as by inhibiting complex I in the mitochondrial respiratory chain (IC 50 = 11.4 μM) [ 8 ]. Under this scenario, the inhibitory effect of this compound on the magnitude and gating of I Na could be of mechanistic, pharmacological, or even clinical relevance [ 15 , 16 , 70 ].…”

“…The NCX activity could be indirectly altered by changes in the magnitude of voltage-gated Na + current ( I Na ) [ 3 , 5 , 6 ]. Therefore, it is worthwhile to reappraise the ionic mechanism of KB-R7943 actions which may exist in different types of ionic currents, particularly at I Na , because significant modifications in magnitude and gating kinetics of this current have been recently investigated for their therapeutic or pharmacological effectiveness [ 11 , 12 , 13 , 14 , 15 , 16 ].…”

Molecular Dynamics Simulations of Ion Permeation in Human Voltage-Gated Sodium Channels

“…A significant step in this direction is represented by the recent boost of deep-learning-based approaches to predict protein structures, , as it has been observed that predicted models of Na v channels are quite close to cryo-EM structures . However, limited differences have been pointed out in specific protein domains, and further experimental and computational studies are necessary to understand their effects. , …”

When the Gates Swing Open Only: Arrhythmia Mutations That Target the Fast Inactivation Gate of Nav1.5

“…These proteins were discovered by Hodgkin and Huxley and have since been studied by a variety of biophysical and biochemical techniques. Eukaryotic Na v s are composed of a large pore-forming α subunit and a smaller auxiliary β subunits [ 2 ]. The α subunit contains 24 transmembrane segments organized in four homologous but not identical domains (DI-DIV) ( Figure 1 ).…”