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

• Published in: Scientific reports Vol. 10; no. 1; p. 14791
• Main Authors: Pajouhesh, H., Beckley, J. T., Delwig, A., Hajare, H. S., Luu, G., Monteleone, D., Zhou, X., Ligutti, J., Amagasu, S., Moyer, B. D., Yeomans, D. C., Du Bois, J., Mulcahy, J. V.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09-09-2020; Nature Publishing Group
• Subjects: 631/154; 631/378; Biochemical analysis; Humanities and Social Sciences; Lysates; multidisciplinary; Neurodegenerative diseases; Protein folding; Proteins; Science; Science (multidisciplinary)
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-71135-2

The voltage-gated sodium channel isoform Na
V
1.7 is highly expressed in dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function Na
V
1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate Na
V
1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting Na
V
1.7 have been advanced to clinical development, no Na
V
1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a Na
V
1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC
50
of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, Na
V
1.1–1.6 and Na
V
1.8. In contrast to other Na
V
1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent in a protocol that favors the resting state of the channel, a protocol that favors the inactivated state, and a high frequency protocol. In a non-human primate study, animals treated with ST-2262 exhibited reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for the design of selective ligands targeting Na
V
1.7.