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Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain

1,2,†, 3,†, 1,2,†, 1,2, 3,4,*, 5,* and 1,2,*
The National & Local Joint Engineering Laboratory of Animal Peptide Drug Development, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
The Key Laboratory of Protein Chemistry and Developmental Biology of Ministry of Education, College of Life Sciences, Hunan Normal University, Changsha 410081, Hunan, China
Life Sciences College of Nanjing Agricultural University, 210095, Jiangsu, China
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming 650223, Yunnan, China
Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology of Hebei Province, College of Life Science, Hebei Normal University, Shijiazhuang 050024, Hebei, China
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Toxins 2018, 10(2), 64;
Received: 27 December 2017 / Revised: 26 January 2018 / Accepted: 31 January 2018 / Published: 2 February 2018
(This article belongs to the Special Issue Toxins and Ion Channels)
PDF [2960 KB, uploaded 26 February 2018]


Jingzhaotoxin-34 (JZTX-34) is a selective inhibitor of tetrodotoxin-sensitive (TTX-S) sodium channels. In this study, we found that JZTX-34 selectively acted on Nav1.7 with little effect on other sodium channel subtypes including Nav1.5. If the DIIS3-S4 linker of Nav1.5 is substituted by the correspond linker of Nav1.7, the sensitivity of Nav1.5 to JZTX-34 extremely increases to 1.05 µM. Meanwhile, a mutant D816R in the DIIS3-S4 linker of Nav1.7 decreases binding affinity of Nav1.7 to JZTX-34 about 32-fold. The reverse mutant R800D at the corresponding position in Nav1.5 greatly increased its binding affinity to JZTX-34. This implies that JZTX-34 binds to DIIS3-S4 linker of Nav1.7 and the critical residue of Nav1.7 is D816. Unlike β-scorpion toxin trapping sodium channel in an open state, activity of JZTX-34 requires the sodium channel to be in a resting state. JZTX-34 exhibits an obvious analgesic effect in a rodent pain model. Especially, it shows a longer duration and is more effective than morphine in hot pain models. In a formalin-induced pain model, JZTX-34 at dose of 2 mg/kg is equipotent with morphine (5 mg/kg) in the first phase and several-fold more effective than morphine in second phase. Taken together, our data indicate that JZTX-34 releases pain by selectively binding to the domain II voltage sensor of Nav1.7 in a closed configuration. View Full-Text
Keywords: peptide toxin; sodium channels; Nav1.7; pain peptide toxin; sodium channels; Nav1.7; pain

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Zeng, X.; Li, P.; Chen, B.; Huang, J.; Lai, R.; Liu, J.; Rong, M. Selective Closed-State Nav1.7 Blocker JZTX-34 Exhibits Analgesic Effects against Pain. Toxins 2018, 10, 64.

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