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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

Journal Article · · Journal of Medicinal Chemistry
ORCiD logo [1];  [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [1];  [3];  [3];  [2];  [1];  [2];  [2];  [1];  [1]; ORCiD logo [1]
  1. Amgen Inc., Thousand Oaks, CA (United States)
  2. Amgen Inc., Cambridge, MA (United States)
  3. Amgen Inc., South San Francisco, CA (United States)
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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.

Research Organization:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES)
Grant/Contract Number:
W-31-109-Eng-38
OSTI ID:
1483893
Journal Information:
Journal of Medicinal Chemistry, Vol. 61, Issue 21; ISSN 0022-2623
Publisher:
American Chemical Society (ACS)Copyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 15 works
Citation information provided by
Web of Science

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Discovery of a selective, state-independent inhibitor of NaV1.7 by modification of guanidinium toxins journal September 2020

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Related Subjects

60 APPLIED LIFE SCIENCES
Modification
Peptides and proteins
Structure activity relationship
Rodent models
Selectivity