Discovery of a Novel Na_v1.7 Inhibitor From Cyriopagopus albostriatus Venom With Potent Analgesic Efficacy.

ABSTRACT: 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_v1.7 contributes to action potential generation and propagation and participates in pain signaling pathway. In this study, we describe the identification of ?-TRTX-Ca2a (Ca2a), a novel 35-residue peptide from the venom of Vietnam spider Cyriopagopus albostriatus (C. albostriatus) that potently inhibits Na_v1.7 (IC₅₀ = 98.1 ± 3.3 nM) with high selectivity against skeletal muscle isoform Na_v1.4 (IC₅₀ > 10 ?M) and cardiac muscle isoform Na_v1.5 (IC₅₀ > 10 ?M). Ca2a did not significantly alter the voltage-dependent activation or fast inactivation of Na_v1.7, but it hyperpolarized the slow inactivation. Site-directed mutagenesis analysis indicated that Ca2a bound with Na_v1.7 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.

SUBMITTER: Zhang Y 

PROVIDER: S-EPMC6198068 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature