AUTHOR=Zhang Yunxiao , Peng Dezheng , Huang Biao , Yang Qiuchu , Zhang Qingfeng , Chen Minzhi , Rong Mingqiang , Liu Zhonghua 

TITLE=Discovery of a Novel Nav1.7 Inhibitor From Cyriopagopus albostriatus Venom With Potent Analgesic Efficacy

JOURNAL=Frontiers in Pharmacology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.01158

DOI=10.3389/fphar.2018.01158

ISSN=1663-9812

ABSTRACT=<p>Spider venoms contain a vast array of bioactive peptides targeting ion channels. A large number of peptides have high potency and selectivity toward sodium channels. Na<sub>v</sub>1.7 contributes to action potential generation and propagation and participates in pain signaling pathway. In this study, we describe the identification of μ-TRTX-Ca2a (Ca2a), a novel 35-residue peptide from the venom of Vietnam spider <italic>Cyriopagopus albostriatus</italic> (<italic>C. albostriatus</italic>) that potently inhibits Na<sub>v</sub>1.7 (IC<sub>50</sub> = 98.1 ± 3.3 nM) with high selectivity against skeletal muscle isoform Na<sub>v</sub>1.4 (IC<sub>50</sub> &gt; 10 μM) and cardiac muscle isoform Na<sub>v</sub>1.5 (IC<sub>50</sub> &gt; 10 μM). Ca2a did not significantly alter the voltage-dependent activation or fast inactivation of Na<sub>v</sub>1.7, but it hyperpolarized the slow inactivation. Site-directed mutagenesis analysis indicated that Ca2a bound with Na<sub>v</sub>1.7 at the extracellular S3–S4 linker of domain II. Meanwhile, Ca2a dose-dependently attenuated pain behaviors in rodent models of formalin-induced paw licking, hot plate test, and acetic acid-induced writhing. This study indicates that Ca2a is a potential lead molecule for drug development of novel analgesics.</p>