Identification and Validation of Small Molecules Inhibiting Human Adenovirus Replication
Human adenovirus (HAdV) mainly causes minor illnesses, but can lead to severe disease and death in both immunocompromised and immunocompetent patients. In such cases, the current standards of treatment often do not improve disease outcome and no approved antiviral therapy against HAdV exists. Since...
Main Author: | |
---|---|
Other Authors: | |
Format: | Others |
Language: | en |
Published: |
Université d'Ottawa / University of Ottawa
2019
|
Subjects: | |
Online Access: | http://hdl.handle.net/10393/39677 http://dx.doi.org/10.20381/ruor-23920 |
id |
ndltd-uottawa.ca-oai-ruor.uottawa.ca-10393-39677 |
---|---|
record_format |
oai_dc |
spelling |
ndltd-uottawa.ca-oai-ruor.uottawa.ca-10393-396772019-10-02T04:32:36Z Identification and Validation of Small Molecules Inhibiting Human Adenovirus Replication Saha, Bratati Parks, Robin Adenovirus Antiviral Small molecule screen Viral epigenetics SAHA Histone deacetylase Cardiotonic steroids Corticosteroids Human adenovirus (HAdV) mainly causes minor illnesses, but can lead to severe disease and death in both immunocompromised and immunocompetent patients. In such cases, the current standards of treatment often do not improve disease outcome and no approved antiviral therapy against HAdV exists. Since HAdV relies on cellular machinery to assist in the progression of the virus lifecycle, we hypothesized that small molecules targeting certain cellular proteins/pathways, without severely affecting cell health, may serve as effective anti-HAdV compounds. Thus, we aimed to identify novel inhibitors of HAdV, and investigate the molecular mechanism to determine new therapeutic targets for intervention in HAdV infection. We first examined the antiviral properties of pan-histone deacetylase (HDAC) inhibitor SAHA and found that the drug affects multiple stages of the HAdV lifecycle, resulting in significant reductions in virus yield. SAHA was effective in decreasing gene expression from clinically relevant HAdV serotypes. Subsequent investigations on the role of HDACs in HAdV infection led us to determine that class I HDAC activity, mainly HDAC2, is necessary for optimal viral gene expression. Using a wildtype-like HAdV reporter construct that allows us to monitor virus replication by fluorescence microscopy, we then designed an efficient system for screening small molecules to identify novel HAdV inhibitors. We screened over 1300 small molecules, and the screen was sensitive enough to detect compounds with both robust and modest antiviral activity. Several positive hits were validated to reduce HAdV gene expression and yield from infected cells. Further investigation on the efficacy of these compounds and the mechanism behind their inhibition of HAdV can lead to the discovery of new pharmacological targets and the development of more effective antivirals. 2019-10-01T12:57:46Z 2019-10-01T12:57:46Z 2019-10-01 Thesis http://hdl.handle.net/10393/39677 http://dx.doi.org/10.20381/ruor-23920 en application/pdf Université d'Ottawa / University of Ottawa |
collection |
NDLTD |
language |
en |
format |
Others
|
sources |
NDLTD |
topic |
Adenovirus Antiviral Small molecule screen Viral epigenetics SAHA Histone deacetylase Cardiotonic steroids Corticosteroids |
spellingShingle |
Adenovirus Antiviral Small molecule screen Viral epigenetics SAHA Histone deacetylase Cardiotonic steroids Corticosteroids Saha, Bratati Identification and Validation of Small Molecules Inhibiting Human Adenovirus Replication |
description |
Human adenovirus (HAdV) mainly causes minor illnesses, but can lead to severe disease and death in both immunocompromised and immunocompetent patients. In such cases, the current standards of treatment often do not improve disease outcome and no approved antiviral therapy against HAdV exists. Since HAdV relies on cellular machinery to assist in the progression of the virus lifecycle, we hypothesized that small molecules targeting certain cellular proteins/pathways, without severely affecting cell health, may serve as effective anti-HAdV compounds. Thus, we aimed to identify novel inhibitors of HAdV, and investigate the molecular mechanism to determine new therapeutic targets for intervention in HAdV infection. We first examined the antiviral properties of pan-histone deacetylase (HDAC) inhibitor SAHA and found that the drug affects multiple stages of the HAdV lifecycle, resulting in significant reductions in virus yield. SAHA was effective in decreasing gene expression from clinically relevant HAdV serotypes. Subsequent investigations on the role of HDACs in HAdV infection led us to determine that class I HDAC activity, mainly HDAC2, is necessary for optimal viral gene expression. Using a wildtype-like HAdV reporter construct that allows us to monitor virus replication by fluorescence microscopy, we then designed an efficient system for screening small molecules to identify novel HAdV inhibitors. We screened over 1300 small molecules, and the screen was sensitive enough to detect compounds with both robust and modest antiviral activity. Several positive hits were validated to reduce HAdV gene expression and yield from infected cells. Further investigation on the efficacy of these compounds and the mechanism behind their inhibition of HAdV can lead to the discovery of new pharmacological targets and the development of more effective antivirals. |
author2 |
Parks, Robin |
author_facet |
Parks, Robin Saha, Bratati |
author |
Saha, Bratati |
author_sort |
Saha, Bratati |
title |
Identification and Validation of Small Molecules Inhibiting Human Adenovirus Replication |
title_short |
Identification and Validation of Small Molecules Inhibiting Human Adenovirus Replication |
title_full |
Identification and Validation of Small Molecules Inhibiting Human Adenovirus Replication |
title_fullStr |
Identification and Validation of Small Molecules Inhibiting Human Adenovirus Replication |
title_full_unstemmed |
Identification and Validation of Small Molecules Inhibiting Human Adenovirus Replication |
title_sort |
identification and validation of small molecules inhibiting human adenovirus replication |
publisher |
Université d'Ottawa / University of Ottawa |
publishDate |
2019 |
url |
http://hdl.handle.net/10393/39677 http://dx.doi.org/10.20381/ruor-23920 |
work_keys_str_mv |
AT sahabratati identificationandvalidationofsmallmoleculesinhibitinghumanadenovirusreplication |
_version_ |
1719259524504748032 |