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Papers of the Week

Papers: 16 Mar 2019 - 22 Mar 2019

Animal Studies, Pharmacology/Drug Development

2019 Apr 19

ACS Chem Biol



Engineering NaV1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation to Enhance Pharmacokinetics.


Murray JK, Wu B, Tegley CM, Nixey TE, Falsey JR, Herberich B, Yin L, Sham K, Long J, Aral J, Cheng Y, Netirojjanakul C, Doherty L, Glaus C, Ikotun T, Li H, Tran L, Soto M, Salimi-Mossavi H, Ligutti J, et al.
ACS Chem Biol. 2019 Apr 19; 14(4):806-818.
PMID: 30875193.


Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel NaV1.7, is being pursued to address the unmet medical need for 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 tarantula venom-derived GpTx-1 toxin peptides with 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 channel isoforms through positional analoging. Here we report utilization of the JzTx-V scaffold in a peptide-antibody conjugate and architectural variations in linker, peptide loading, and antibody attachment site. We found conjugates with 100x improved in vitro potency relative to complementary GpTx-1 analogs, but pharmacokinetic and bioimaging analyses of these JzTx-V conjugates revealed a shorter than expected plasma half-life in vivo with accumulation in the liver. In an attempt to increase circulatory serum levels, we sought the reduction of the net +6 charge of the JzTx-V scaffold whilst retaining a desirable NaV in vitro activity profile. The conjugate of a JzTx-V peptide analog with a +2 formal charge maintained NaV1.7 potency with 18-fold improved plasma exposure in rodents. Balancing the loss in peptide and conjugate potency associated with the reduction of net charge necessary for improved target exposure resulted in a compound with moderate activity in a NaV1.7-dependent pharmacodynamic model but requires further optimization to identify a conjugate that can fully engage NaV1.7 in vivo.