2013
DOI: 10.1073/pnas.1220844110
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Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels

Abstract: Significance Voltage-gated sodium (Na v ) channels contribute to physiological and pathophysiological electrical signaling in nerve and muscle cells. Because Na v channel isoforms exhibit tissue-specific expression, subtype selective modulation of this channel family provides important drug development opportunities. However, most available Na v channel modulators are unable to distinguish between Na v … Show more

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Cited by 218 publications
(300 citation statements)
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“…We found that Hm1a inhibits fast and slow inactivation, whereas a small-molecule inhibitor, ICA-121431 (20), acts solely on slow inactivation through interactions with the same voltage sensor, thus supporting a role for VSDIV in both fast and slow inactivation. Moreover, we show that a Na v 1.1 mutant lacking fast inactivation has dramatic effects on slow inactivation, further suggesting coupling between these processes (21).…”
Section: Ica-121431mentioning
confidence: 63%
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“…We found that Hm1a inhibits fast and slow inactivation, whereas a small-molecule inhibitor, ICA-121431 (20), acts solely on slow inactivation through interactions with the same voltage sensor, thus supporting a role for VSDIV in both fast and slow inactivation. Moreover, we show that a Na v 1.1 mutant lacking fast inactivation has dramatic effects on slow inactivation, further suggesting coupling between these processes (21).…”
Section: Ica-121431mentioning
confidence: 63%
“…ICA-121431 (ICA) is a small molecule inhibitor of Na v 1.1 and Na v 1.3 that has been shown to target extracellular amino acids within S2 and S3 in VSDIV, a locus also required for Hm1a efficacy (10,20). Indeed, we found that Na v 1.4 can be rendered ICA-sensitive by replacing the S1-S2 and S3-S4 loops of VSDIV with those from Na v 1.1 (Fig.…”
Section: Resultsmentioning
confidence: 91%
“…Ion channels are responsible for a number of channelopathies (i.e., pathological conditions of various origins), including genetic channelopathies caused by malfunctioning ion channels (78). Nevertheless, despite recent efforts resulting in the discovery of novel potential drugs targeting ion channels (39,40), this class of proteins remains quite underexploited in drug discovery because it poses significant challenges (78)(79)(80)(81). For many years,…”
Section: Discussionmentioning
confidence: 99%
“…Finally, substrate-mimicking strategies, traditionally adopted for enzymes, are hardly an option for ion channels: Competition with the permeant ion in the selectivity filter can be attained only by another ion or by small fragments. Recent advances in the biophysical characterization and screening of ion channels, together with continuing progress in biomolecular simulations, have paved the way for successful drug design campaigns (39,40,82) that have made ion channels pharmaceutically tractable, as well as attractive, targets. Notably, targeting ion channels increased the therapeutic options in areas such as cardiovascular diseases, neuropathic pain, diabetes, and cancer (79,81).…”
Section: S1mentioning
confidence: 99%
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