UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

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

Penny, CJ; Vassileva, K; Jha, A; Yuan, Y; Chee, X; Yates, E; Mazzon, M; ... Patel, S; + view all (2019) Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research , 1866 (7) pp. 1151-1161. 10.1016/j.bbamcr.2018.10.022. Green open access

[img]
Preview
Text
Penny_-s2.0-S0167488918304993-main.pdf - Accepted version

Download (9MB) | Preview

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.

Type: Article
Title: Mining of Ebola virus entry inhibitors identifies approved drugs as two-pore channel pore blockers
Location: Netherlands
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bbamcr.2018.10.022
Publisher version: https://doi.org/10.1016/j.bbamcr.2018.10.022
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Ca(2+), Ebola virus, Lysosomes, NAADP, TPC2, Virtual screening
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Cell and Developmental Biology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10061505
Downloads since deposit
33Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item