Engineering Na V 1.7 Inhibitory JzTx-V Peptides with a Potency and Basicity Profile Suitable for Antibody Conjugation To Enhance Pharmacokinetics

Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel Na 1.7, 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 previ...

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Published in:ACS chemical biology 2019-04, Vol.14 (4), p.806-818
Main Authors: Murray, Justin K, Wu, Bin, Tegley, Christopher M, Nixey, Thomas E, Falsey, James R, Herberich, Brad, Yin, Li, Sham, Kelvin, Long, Jason, Aral, Jennifer, Cheng, Yuan, Netirojjanakul, Chawita, Doherty, Liz, Glaus, Charles, Ikotun, Tayo, Li, Hongyan, Tran, Linh, Soto, Marcus, Salimi-Moosavi, Hossein, Ligutti, Joseph, Amagasu, Shanti, Andrews, Kristin L, Be, Xuhai, Lin, Min-Hwa Jasmine, Foti, Robert S, Ilch, Christopher P, Youngblood, Beth, Kornecook, Thomas J, Karow, Margaret, Walker, Kenneth W, Moyer, Bryan D, Biswas, Kaustav, Miranda, Les P
Format: Article
Language:English
Subjects:
Animals
Antibodies - chemistry
Drug Discovery
Humans
Immunoconjugates - chemistry
Immunoconjugates - pharmacokinetics
Male
Mice
Molecular Targeted Therapy
NAV1.7 Voltage-Gated Sodium Channel - immunology
NAV1.7 Voltage-Gated Sodium Channel - metabolism
Peptides - chemistry
Peptides - pharmacokinetics
Spider Venoms - chemistry
Spider Venoms - pharmacokinetics
Voltage-Gated Sodium Channel Blockers - chemistry
Voltage-Gated Sodium Channel Blockers - pharmacokinetics
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Summary:Drug discovery research on new pain targets with human genetic validation, including the voltage-gated sodium channel Na 1.7, 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 Na 1.7 inhibitory peptide-antibody conjugates with tarantula venom-derived GpTx-1 toxin peptides with an extended half-life (80 h) in rodents but only moderate in vitro activity (hNa 1.7 IC = 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 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 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 while retaining a desirable Na in vitro activity profile. The conjugate of a JzTx-V peptide analogue with a +2 formal charge maintained Na 1.7 potency with 18-fold improved plasma exposure in rodents. Balancing the loss of 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 Na 1.7-dependent pharmacodynamic model but requires further optimization to identify a conjugate that can fully engage Na 1.7 in vivo.
ISSN:1554-8929
1554-8937
DOI:10.1021/acschembio.9b00183