Engineering NaV1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation To Enhance Pharmacokinetics
2019
Drug discovery research on new pain targets with
human geneticvalidation, including the voltage-gated
sodium channelNaV1.7, is being pursued to address the unmet medical need with respect to chronic pain and the rising
opioid epidemic. As part of early research efforts on this front, we have previously developed NaV1.7 inhibitory peptide–antibody conjugates with
tarantulavenom-derived GpTx-1 toxin peptides with an extended half-life (80 h) in rodents but only moderate in vitro activity (hNaV1.7 IC50 = 250 nM) and without in vivo activity. We identified the more potent peptide JzTx-V from our natural peptide collection and improved its selectivity against other
sodium channelisoforms through positional analogueing. Here we report utilization of the JzTx-V scaffold in a peptide–antibody conjugate and architectural variations in the linker, peptide loading, and antibody attachment site. We found conjugates with 100-fold improved in vitro potency relative to those of complementary GpTx-1 analogues, but ph...
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