The Nav1.7 channel represents a promising target for pain relief.In the recent decades,a number of Nav1.7 channel inhibitors have been developed.According to the effects on channel kinetics,these inhibitors could be divided into two major classes:reducing activation or enhancing inactivation.To date,however,only several inhibitors have moved forward into phase 2 clinical trials and most of them display a less than ideal analgesic efficacy,thus intensifying the controversy regarding if an ideal candidate should preferentially affect the activation or inactivation state.In the present study,we investigated the action mechanisms of a recently clinically confirmed inhibitor CNV1014802 using both electrophysiology and site-directed mutagenesis.We found that CNV1014802 inhibited Nav1.7 channels through stabilizing a nonconductive inactivated state.When the cells expressing Nav1.7 channels were hold at 70 mV or 120 mV,the half maximal inhibitory concentration (IC50) values (with 95％ confidence limits) were 1.77 (1.20-2.33)and 71.66 (46.85-96.48) pmol/L,respectively.This drug caused dramatic hyperpolarizing shift of channel inactivation but did not affect activation.Moreover,CNV1014802 accelerated the onset of inactivation and delayed the recovery from inactivation.Notably,application of CNV1014802 (30 pmol/L) could rescue the Nav1.7 mutations expressed in CHO cells that cause paroxysmal extreme pain disorder (PEPD),thereby restoring the impaired inactivation to those of the wild-type channel.Our study demonstrates that CNV1014802 enhances the inactivation but does not reduce the activation of Nav1.7 channels,suggesting that identifying inhibitors that preferentially affect inactivation is a promising approach for developing drugs targeting Nav1.7.