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. 2020 Oct 20;63(21):12773–12785. doi: 10.1021/acs.jmedchem.0c01107

Figure 5.

Figure 5

Kinetics of NaV inhibition by monovalent and bivalent ligands at hNaV1.4 and hNaV1.7. (A) On-rate measurements for S-m3-HwTx-IV and AzK-KIIIA alone or conjugated to the PEG80 linker, and bivalent ligands [m3-HwTx-IV]-[PEG60]-[K-KIIIA] and [m3-HwTx-IV]-[PEG80]-[K-KIIIA]. On-rates were calculated from the fitted exponentials (dashed lines). (B) Off-rate measurements of precursor peptides S-m3-HwTx-IV and AzK-KIIIA and bivalent ligands [m3-HwTx-IV]-[PEG60]-[K-KIIIA] and [m3-HwTx-IV]-[PEG80]-[K-KIIIA] over hNaV1.4 and S-m3-HwTx-IV, AzK-KIIIA, and bivalent ligand [m3-HwTx-IV]-[PEG80]-[K-KIIIA] over hNaV1.7. Off-rates were calculated from the fitted exponentials (dashed lines). (C) Channel currents measured at the end of a 25 min ligand washout period. For these experiments, we used HEK293 cells that stably express either NaV1.7 or NaV1.4 along with the β1 auxiliary subunit. Data points are the mean ± SEM of three to five independent experiments. Statistical significance was determined by one-way analysis of variance followed by Tukey’s multiple-comparison test. ****P < 0.0001; *P = 0.019.