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Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level


Stadler, K; Ha, H R; Ciminale, V; Spirli, C; Saletti, G; Schiavon, M; Bruttomesso, D; Bigler, L; Follath, F; Pettenazzo, A; Baritussio, A (2008). Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level. American Journal of Respiratory Cell and Molecular Biology, 39(2):142-149.

Abstract

Amiodarone interferes with the endocytic pathway, inhibits proteolysis, and causes the formation of vacuoles, but uptake and intracellular distribution of the drug, origin of vacuoles, and functional consequences of amiodarone accumulation remain unclear.
Our objective was to study amiodarone uptake, clarify the origin of vacuoles,andinvestigate the effect of amiodaroneonthe life cycle of the coronavirus responsible for the Severe Acute Respiratory Syndrome (SARS), which, to enter cells, relies on the proteolytic cleavage of a viral spike protein by the endosomal proteinase cathepsin L. Using alveolar macrophages, we studied uptake of
125I-amiodarone and 125I-B2, an analog lacking the lateral group diethylamino-b-ethoxy, and analyzed the effects of amiodarone on the distribution of endosomal markers and on the uptake of an acidotropic dye. Furthermore, using Vero cells, we tested the impact of amiodarone on the in vitro spreading of the SARS coronavirus.We found that
(1) amiodarone associates with different cell membranes and accumulates in acidic organelles;
(2) the diethylamino-b-ethoxy group is an important determinant of uptake;
(3) vacuoles forming upon exposure to amiodarone are enlarged late endosomes;
(4) amiodarone inhibits the spreading in vitro of SARS coronavirus; and
(5) trypsin cleavage of the viral spike protein before infection, which permits virus entry through the plasma membrane, does not impair amiodarone antiviral activity. We conclude that amiodarone alters late compartments of the endocytic pathway and inhibits SARS
coronavirus infection by acting after the transit of the virus through endosomes.

Amiodarone interferes with the endocytic pathway, inhibits proteolysis, and causes the formation of vacuoles, but uptake and intracellular distribution of the drug, origin of vacuoles, and functional consequences of amiodarone accumulation remain unclear.
Our objective was to study amiodarone uptake, clarify the origin of vacuoles,andinvestigate the effect of amiodaroneonthe life cycle of the coronavirus responsible for the Severe Acute Respiratory Syndrome (SARS), which, to enter cells, relies on the proteolytic cleavage of a viral spike protein by the endosomal proteinase cathepsin L. Using alveolar macrophages, we studied uptake of
125I-amiodarone and 125I-B2, an analog lacking the lateral group diethylamino-b-ethoxy, and analyzed the effects of amiodarone on the distribution of endosomal markers and on the uptake of an acidotropic dye. Furthermore, using Vero cells, we tested the impact of amiodarone on the in vitro spreading of the SARS coronavirus.We found that
(1) amiodarone associates with different cell membranes and accumulates in acidic organelles;
(2) the diethylamino-b-ethoxy group is an important determinant of uptake;
(3) vacuoles forming upon exposure to amiodarone are enlarged late endosomes;
(4) amiodarone inhibits the spreading in vitro of SARS coronavirus; and
(5) trypsin cleavage of the viral spike protein before infection, which permits virus entry through the plasma membrane, does not impair amiodarone antiviral activity. We conclude that amiodarone alters late compartments of the endocytic pathway and inhibits SARS
coronavirus infection by acting after the transit of the virus through endosomes.

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16 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiology
07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:610 Medicine & health
540 Chemistry
Uncontrolled Keywords:amiodarone; endocytic pathway; SARS coronavirus
Language:English
Date:28 February 2008
Deposited On:17 May 2010 21:30
Last Modified:05 Apr 2016 13:21
Publisher:American Thoracic Society
ISSN:1044-1549
Publisher DOI:10.1165/rcmb.2007-0217OC
Official URL:http://www.atsjournals.org
Permanent URL: http://doi.org/10.5167/uzh-20798

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