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bioRxiv · 10.1101/869206

Discovery of a Selective, State-Independent Inhibitor of NaV1.7 by Modification of Guanidinium Toxins

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.
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Abstract

The voltage-gated sodium channel isoform NaV1.7 is highly expressed in small diameter dorsal root ganglion neurons and is obligatory for nociceptive signal transmission. Genetic gain-of-function and loss-of-function NaV1.7 mutations have been identified in select individuals, and are associated with episodic extreme pain disorders and insensitivity to pain, respectively. These findings implicate NaV1.7 as a key pharmacotherapeutic target for the treatment of pain. While several small molecules targeting NaV1.7 have been advanced to clinical development, no NaV1.7-selective compound has shown convincing efficacy in clinical pain applications. Here we describe the discovery and characterization of ST-2262, a NaV1.7 inhibitor that blocks the extracellular vestibule of the channel with an IC50 of 72 nM and greater than 200-fold selectivity over off-target sodium channel isoforms, NaV1.1-1.6 and NaV1.8. In contrast to other NaV1.7 inhibitors that preferentially inhibit the inactivated state of the channel, ST-2262 is equipotent against resting and inactivated protein conformers. In a non-human primate model, animals treated with ST-2262 exhibit markedly reduced sensitivity to noxious heat. These findings establish the extracellular vestibule of the sodium channel as a viable receptor site for selective ligand design and provide insight into the pharmacology of state-independent inhibition of NaV1.7. Significance StatementPain is among the most common reasons for seeking medical care, yet many frequently prescribed drugs, particularly the opioids, cause problematic side effects and carry a risk of addiction. Voltage-gated sodium ion channels (NaVs) have emerged as promising targets for the development of non-opioid pain medicines. NaVs are involved in the propagation of electrical signals along neurons throughout the body. Humans born without a functional copy of one sodium channel subtype, NaV1.7, are unable to experience most types of pain. In the present work, we disclose the discovery and characterization of a selective inhibitor of NaV1.7 that reduces sensitivity to a painful thermal stimulus in non-human primates. Findings from this work may help guide the development of novel, non-addictive drug candidates as alternatives to opioids.

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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.. 2019-12-10. Discovery of a Selective, State-Independent Inhibitor of NaV1.7 by Modification of Guanidinium Toxins. https://doi.org/10.1101/869206

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