دورية أكاديمية
أعرض في EDS

Discovery of a selective, state-independent inhibitor of Na V 1.7 by modification of guanidinium toxins.

التفاصيل البيبلوغرافية
العنوان: Discovery of a selective, state-independent inhibitor of Na V 1.7 by modification of guanidinium toxins.
المؤلفون: Pajouhesh H; SiteOne Therapeutics, South San Francisco, CA, 94080, USA., Beckley JT; SiteOne Therapeutics, Bozeman, MT, 59715, USA., Delwig A; SiteOne Therapeutics, South San Francisco, CA, 94080, USA., Hajare HS; Department of Chemistry, Stanford University, Stanford, CA, 94305, USA., Luu G; SiteOne Therapeutics, South San Francisco, CA, 94080, USA., Monteleone D; SiteOne Therapeutics, South San Francisco, CA, 94080, USA., Zhou X; SiteOne Therapeutics, South San Francisco, CA, 94080, USA., Ligutti J; Neuroscience Department, Amgen Research, Thousand Oaks, CA, 91320, USA., Amagasu S; Neuroscience Department, Amgen Research, Thousand Oaks, CA, 91320, USA., Moyer BD; Neuroscience Department, Amgen Research, Thousand Oaks, CA, 91320, USA., Yeomans DC; Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, 94305, USA., Du Bois J; Department of Chemistry, Stanford University, Stanford, CA, 94305, USA., Mulcahy JV; SiteOne Therapeutics, South San Francisco, CA, 94080, USA. john.mulcahy@site1therapeutics.com.
المصدر: Scientific reports [Sci Rep] 2020 Sep 09; Vol. 10 (1), pp. 14791. Date of Electronic Publication: 2020 Sep 09.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE
أسماء مطبوعة: Original Publication: London : Nature Publishing Group, copyright 2011-
مواضيع طبية MeSH: Guanidine/*chemistry , NAV1.7 Voltage-Gated Sodium Channel/*chemistry , Sodium Channel Blockers/*chemistry , Sodium Channel Blockers/*pharmacology, Animals ; Drug Discovery ; Ganglia, Spinal/metabolism ; Humans ; NAV1.1 Voltage-Gated Sodium Channel/chemistry ; NAV1.2 Voltage-Gated Sodium Channel/chemistry ; NAV1.3 Voltage-Gated Sodium Channel/chemistry ; NAV1.4 Voltage-Gated Sodium Channel/chemistry ; NAV1.5 Voltage-Gated Sodium Channel/chemistry ; NAV1.6 Voltage-Gated Sodium Channel/chemistry ; NAV1.8 Voltage-Gated Sodium Channel/chemistry ; Protein Structure, Secondary
مستخلص: 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.
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معلومات مُعتمدة: R01 GM117263 United States GM NIGMS NIH HHS; R44 NS081887 United States NS NINDS NIH HHS; R01 GM117263-01A1 United States NH NIH HHS
المشرفين على المادة: 0 (NAV1.1 Voltage-Gated Sodium Channel)
0 (NAV1.2 Voltage-Gated Sodium Channel)
0 (NAV1.3 Voltage-Gated Sodium Channel)
0 (NAV1.4 Voltage-Gated Sodium Channel)
0 (NAV1.5 Voltage-Gated Sodium Channel)
0 (NAV1.6 Voltage-Gated Sodium Channel)
0 (NAV1.7 Voltage-Gated Sodium Channel)
0 (NAV1.8 Voltage-Gated Sodium Channel)
0 (Sodium Channel Blockers)
JU58VJ6Y3B (Guanidine)
تواريخ الأحداث: Date Created: 20200910 Date Completed: 20210517 Latest Revision: 20240330
رمز التحديث: 20240330
مُعرف محوري في PubMed: PMC7481244
DOI: 10.1038/s41598-020-71135-2
PMID: 32908170
قاعدة البيانات: MEDLINE
الوصف
تدمد:2045-2322
DOI:10.1038/s41598-020-71135-2