Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker

Tochitsky, I.; Jo, S.; Andrews, N.; Kotoda, M.; Doyle, B.; Shim, J.; Talbot, S.; Roberson, D. P.; Lee, J.; Haste, L.; Jordan, S. M.; Levy, B.; Bean, B. P.; J. Woolf, C.

doi:10.1101/2020.12.07.414763

bioRxiv · 10.1101/2020.12.07.414763

Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker

Tochitsky, I.·Jo, S.·Andrews, N.·Kotoda, M.·Doyle, B.·Shim, J.·Talbot, S.·Roberson, D. P.·Lee, J.·Haste, L.·Jordan, S. M.·Levy, B.·Bean, B. P.·J. Woolf, C.

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Abstract

Although multiple diseases of the respiratory system cause cough, there are few effective treatments for this common condition. We previously developed a strategy to treat pain and itch via the long-lasting inhibition of nociceptor sensory neurons with QX-314, a cationic sodium channel blocker that selectively enters only into activated nociceptors by permeating through the endogenous TRPV1 and TRPA1 large pore ion channels they express. In this study we design and characterize BW-031, a novel cationic compound with [~]6-fold greater potency than QX-314 for inhibiting sodium channels when introduced inside cells and with minimal extracellular activity. We show that inhalation of aerosolized BW-031 effectively inhibits citric acid-induced cough in an allergic inflammation guinea pig cough model. These data support the use of charged sodium channel blockers for the selective inhibition of airway sensory neurons with activated large pore channels as a novel targeted therapy for treating cough.

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Tochitsky, I., Jo, S., Andrews, N., Kotoda, M., Doyle, B., Shim, J., Talbot, S., Roberson, D. P., Lee, J., Haste, L., Jordan, S. M., Levy, B., Bean, B. P., J. Woolf, C.. 2020-12-07. Inhibiting cough by silencing large pore-expressing airway sensory neurons with a charged sodium channel blocker. https://doi.org/10.1101/2020.12.07.414763

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