About: Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers

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type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers
Creator	Marsh, Mark Mazzon, Michela Chee, Xavier Jha, Archana Muallem, Shmuel Patel, Sandip Rahman, Taufiq Vassileva, Kristin Yates, Elizabeth Yuan, Yu Haiech, Jacques Heizmann, Claus Kilpatrick, Bethan Krebs, Joachim Penny, Christopher
Source	Elsevier; Medline; PMC
abstract	Abstract Two-pore channels (TPCs) are Ca2+-permeable ion channels localised to the endo-lysosomal system where they regulate trafficking of various cargoes including viruses. As a result, TPCs are emerging as important drug targets. However, their pharmacology is ill-defined. There are no approved drugs to target them. And their mechanism of ligand activation is largely unknown. Here, we identify a number of FDA-approved drugs as TPC pore blockers. Using a model of the pore of human TPC2 based on recent structures of mammalian TPCs, we virtually screened a database of ~1500 approved drugs. Because TPCs have recently emerged as novel host factors for Ebola virus entry, we reasoned that Ebola virus entry inhibitors may exert their effects through inhibition of TPCs. Cross-referencing hits from the TPC virtual screen with two recent high throughput anti-Ebola screens yielded approved drugs targeting dopamine and estrogen receptors as common hits. These compounds inhibited endogenous NAADP-evoked Ca2+ release from sea urchin egg homogenates, NAADP-mediated channel activity of TPC2 re-routed to the plasma membrane, and PI(3,5)P2-mediated channel activity of TPC2 expressed in enlarged lysosomes. Mechanistically, single channel analyses showed that the drugs reduced mean open time consistent with a direct action on the pore. Functionally, drug potency in blocking TPC2 activity correlated with inhibition of Ebola virus-like particle entry. Our results expand TPC pharmacology through the identification of approved drugs as novel blockers, support a role for TPCs in Ebola virus entry, and provide insight into the mechanisms underlying channel regulation. This article is part of a Special Issue entitled: ECS Meeting edited by Claus Heizmann, Joachim Krebs and Jacques Haiech.
has issue date	2019-07-31(xsd:dateTime)
bibo:doi	10.1016/j.bbamcr.2018.10.022
bibo:pmid	30408544
has license	els-covid
sha1sum (hex)	91dd047f452e6df2ef627b5eb489347d621247a2
schema:url	https://doi.org/10.1016/j.bbamcr.2018.10.022
resource representing a document's title	Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers
has PubMed Central identifier	PMC7114365
has PubMed identifier	30408544
schema:publication	Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
resource representing a document's body	covid:91dd047f452e6df2ef627b5eb489347d621247a2#body_text
is schema:about of	named entity 'DRUGS' named entity 'receptors' named entity 'drugs' named entity 'blockers' named entity 'There' named entity 'blockers' named entity 'pharmacology' named entity 'However' named entity 'VIRUS ENTRY' named entity 'ENTRY INHIBITORS' named entity 'HAVE' named entity 'FDA' named entity 'OUR' named entity 'PHARMACOLOGY' named entity 'WHERE' named entity 'ENDOGENOUS' named entity '283' named entity 'DATABASE' named entity 'EBOLA' named entity 'TIME' named entity 'IDENTIFY' named entity 'HOST' named entity 'HERE' named entity 'TPC' named entity 'REGULATION' named entity 'SEA URCHIN' named entity 'IDENTIFICATION' named entity 'SUPPORT' named entity 'MECHANISM' named entity 'NUMBER OF' named entity 'RECENTLY' named entity 'THESE' named entity 'APPROVED' named entity 'CHANNEL ACTIVITY' named entity 'ROLE' named entity 'ILL-DEFINED' named entity 'LOCALISED' named entity 'VIRUS ENTRY' named entity 'REGULATE' named entity 'CORRELATED' named entity 'CONSISTENT WITH' named entity 'ESTROGEN RECEPTORS' named entity 'VARIOUS' named entity 'APPROVED' named entity 'CHANNELS' named entity 'RECENT' named entity 'EXPRESSED' named entity 'COMMON' named entity 'SYSTEM' named entity 'EBOLA VIRUS' named entity 'UNDERLYING' named entity 'INHIBITION' named entity 'EBOLA VIRUS' named entity 'LIGAND' named entity 'MAMMALIAN' named entity 'DIRECT' named entity 'NAADP' named entity 'CROSS' named entity 'STRUCTURES' named entity 'VIRTUAL' named entity 'ENLARGED' named entity '2C5' named entity 'EFFECTS' named entity 'SINGLE' named entity 'ACTION' named entity 'TPC2' named entity 'RELEASE'

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