Discovery of Tarantula Venom-Derived NaV 1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis
Abstract
Inhibitors of the voltage-gated sodium channel NaV1.7 are being investigated as pain therapeutics due to compelling human genetics. We previously identified NaV1.7-inhibitory peptides GpTx-1 and JzTx-V from tarantula venom screens. Potency and selectivity were modulated through attribute-based positional scans of native residues via chemical synthesis. In this paper, we report JzTx-V lead optimization to identify a pharmacodynamically active peptide variant. Molecular docking of peptide ensembles from NMR into a homology model-derived NaV1.7 structure supported prioritization of key residues clustered on a hydrophobic face of the disulfide-rich folded peptide for derivatization. Replacing Trp24 with 5-Br- Trp24 identified lead peptides with activity in electrophysiology assays in engineered and neuronal cells. 5-Br-Trp24 containing peptide AM-6120 was characterized in X-ray crystallography and pharmacokinetic studies and blocked histamine-induced pruritis in mice after subcutaneous administration, demonstrating systemic NaV1.7-dependent pharmacodynamics. Our data suggests a need for high target coverage based on plasma exposure for impacting in vivo end points with selectivity-optimized peptidic NaV1.7 inhibitors.
- Authors:
-
[1];
[1]
- Amgen Inc., Thousand Oaks, CA (United States)
- Amgen Inc., Cambridge, MA (United States)
- Amgen Inc., South San Francisco, CA (United States)
- Publication Date:
- Research Org.:
- Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
- Sponsoring Org.:
- USDOE Office of Science (SC), Basic Energy Sciences (BES)
- OSTI Identifier:
- 1483893
- Grant/Contract Number:
- W-31-109-Eng-38
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Medicinal Chemistry
- Additional Journal Information:
- Journal Volume: 61; Journal Issue: 21; Journal ID: ISSN 0022-2623
- Publisher:
- American Chemical Society (ACS)
- Country of Publication:
- United States
- Language:
- ENGLISH
- Subject:
- 60 APPLIED LIFE SCIENCES; Modification; Peptides and proteins; Structure activity relationship; Rodent models; Selectivity
Citation Formats
Wu, Bin, Murray, Justin K., Andrews, Kristin L., Sham, Kelvin, Long, Jason, Aral, Jennifer, Ligutti, Joseph, Amagasu, Shanti, Liu, Dong, Zou, Anruo, Min, Xiaoshan, Wang, Zhulun, Ilch, Christopher P., Kornecook, Thomas J., Lin, Min-Hwa Jasmine, Be, Xuhai, Miranda, Les P., Moyer, Bryan D., and Biswas, Kaustav. Discovery of Tarantula Venom-Derived NaV 1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis. United States: N. p., 2018.
Web. doi:10.1021/acs.jmedchem.8b00736.
Wu, Bin, Murray, Justin K., Andrews, Kristin L., Sham, Kelvin, Long, Jason, Aral, Jennifer, Ligutti, Joseph, Amagasu, Shanti, Liu, Dong, Zou, Anruo, Min, Xiaoshan, Wang, Zhulun, Ilch, Christopher P., Kornecook, Thomas J., Lin, Min-Hwa Jasmine, Be, Xuhai, Miranda, Les P., Moyer, Bryan D., & Biswas, Kaustav. Discovery of Tarantula Venom-Derived NaV 1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis. United States. https://doi.org/10.1021/acs.jmedchem.8b00736
Wu, Bin, Murray, Justin K., Andrews, Kristin L., Sham, Kelvin, Long, Jason, Aral, Jennifer, Ligutti, Joseph, Amagasu, Shanti, Liu, Dong, Zou, Anruo, Min, Xiaoshan, Wang, Zhulun, Ilch, Christopher P., Kornecook, Thomas J., Lin, Min-Hwa Jasmine, Be, Xuhai, Miranda, Les P., Moyer, Bryan D., and Biswas, Kaustav. Mon .
"Discovery of Tarantula Venom-Derived NaV 1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis". United States. https://doi.org/10.1021/acs.jmedchem.8b00736. https://www.osti.gov/servlets/purl/1483893.
@article{osti_1483893,
title = {Discovery of Tarantula Venom-Derived NaV 1.7-Inhibitory JzTx-V Peptide 5-Br-Trp24 Analogue AM-6120 with Systemic Block of Histamine-Induced Pruritis},
author = {Wu, Bin and Murray, Justin K. and Andrews, Kristin L. and Sham, Kelvin and Long, Jason and Aral, Jennifer and Ligutti, Joseph and Amagasu, Shanti and Liu, Dong and Zou, Anruo and Min, Xiaoshan and Wang, Zhulun and Ilch, Christopher P. and Kornecook, Thomas J. and Lin, Min-Hwa Jasmine and Be, Xuhai and Miranda, Les P. and Moyer, Bryan D. and Biswas, Kaustav},
abstractNote = {Inhibitors of the voltage-gated sodium channel NaV1.7 are being investigated as pain therapeutics due to compelling human genetics. We previously identified NaV1.7-inhibitory peptides GpTx-1 and JzTx-V from tarantula venom screens. Potency and selectivity were modulated through attribute-based positional scans of native residues via chemical synthesis. In this paper, we report JzTx-V lead optimization to identify a pharmacodynamically active peptide variant. Molecular docking of peptide ensembles from NMR into a homology model-derived NaV1.7 structure supported prioritization of key residues clustered on a hydrophobic face of the disulfide-rich folded peptide for derivatization. Replacing Trp24 with 5-Br- Trp24 identified lead peptides with activity in electrophysiology assays in engineered and neuronal cells. 5-Br-Trp24 containing peptide AM-6120 was characterized in X-ray crystallography and pharmacokinetic studies and blocked histamine-induced pruritis in mice after subcutaneous administration, demonstrating systemic NaV1.7-dependent pharmacodynamics. Our data suggests a need for high target coverage based on plasma exposure for impacting in vivo end points with selectivity-optimized peptidic NaV1.7 inhibitors.},
doi = {10.1021/acs.jmedchem.8b00736},
journal = {Journal of Medicinal Chemistry},
number = 21,
volume = 61,
place = {United States},
year = {Mon Oct 22 00:00:00 EDT 2018},
month = {Mon Oct 22 00:00:00 EDT 2018}
}
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Works referencing / citing this record:
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