Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaV1.7

Abstract

Voltage-gated sodium ion channel subtype 1.7 (Na_V1.7) is a high interest target for the discovery of non-opioid analgesics. Compelling evidence from human genetic data, particularly the finding that persons lacking functional Na_V1.7 are insensitive to pain, has spurred considerable effort to develop selective inhibitors of this Na⁺ ion channel target as analgesic medicines. Recent clinical setbacks and disappointing performance of preclinical compounds in animal pain models, however, have led to skepticism around the potential of selective Na_V1.7 inhibitors as human therapeutics. In this Perspective, we discuss the attributes and limitations of recently disclosed investigational drugs targeting Na_V1.7 and review evidence that, by better understanding the requirements for selectivity and target engagement, the opportunity to deliver effective analgesic medicines targeting Na_V1.7 endures.

Figure 1

Contribution of Na_V1.7, Na_V1.8 and Na_V1.9 to the action potential in peripheral nociceptive neurons, adapted from Bennett et al. Na_V1.7 and Na_V1.9 function as threshold channels, amplifying small depolarizations driven by upstream ion channels.^,, Na_V1.7 also contributes to the rising phase of the action potential. Na_V1.8 is activated at more depolarized potentials near 0 mV, contributes the majority of current to the rising phase of the action potential, and is capable of high frequency firing due to rapid recovery from inactivation.^–

Figure 2

A) The Na_V α-subunit consists of four homologous domains arranged symmetrically around an ion-conducting pore. Each domain contains six transmembrane alpha helices, S1–S6. The voltage sensor (S4, green cylinder) partially traverses the membrane in response to voltage changes. B) Activation of domain I–III voltage sensors is coupled to Na_V channel opening. Activation of domain IV is coupled to movement of the inactivation motif (IFM) and fast-inactivation.

Figure 3

Approximate binding sites of compounds targeting Na_V1.7 overlaid on cryo-EM structure of hNa_V1.7-β1-β2 complex. (Left) Extracellular view of hNa_V1.7. (Right) Cross section through hNa_V1.7. Approximate ligand binding sites: (1) extracellular vestibule, (2) VSD II, (3) local anesthetic binding site, (4) VSD IV.

Figure 4

Potency and selectivity of Na_V1.7 inhibitors advanced to clinical development. ^,,–

Figure 5

Na_V1.7 inhibitors targeting VSD IV evaluated in rodent pain behavior models. “+” indicates effective in PD model. “–” indicates not effective. *K_d of GX-585 against mouse TTX-resistant current = 22 µM **K_d of GX-201 against mouse TTX-resistant current = 13 µM. ^,–,–,

Figure 6

PK/PD relationship of GX-585 (13) and GX-201 (14) in mouse models of thermal, mechanical, chemical and inflammatory pain. “+” indicates effective in PD model. “–” indicates not effective. Ave. C_p = average total plasma concentration.

Figure 7

Selective cystine knot toxins that bind to VSD II in Na_V1.7. “+” indicates effective in PD model. “–” indicates not effective. r = rat. m = mouse.^–

Figure 8

Natural and synthetic guanidinium compounds that bind to the extracellular pore. ^,,–