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Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication

Beatrice Mercorelli, Anna Luganini, Giulio Nannetti Orcid Logo, Oriana Tabarrini, Giorgio Palù, Giorgio Gribaudo, Arianna Loregian

Cell Chemical Biology, Volume: 23, Issue: 3, Pages: 340 - 351

Swansea University Author: Giulio Nannetti Orcid Logo

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DOI (Published version): 10.1016/j.chembiol.2015.12.012

Abstract

New targets for antiviral strategies are needed against human cytomegalovirus (HCMV), a major human pathogen. A cell-based screen aimed at finding inhibitors of the viral transcription factor Immediate-Early 2 (IE2) was performed in HCMV-infected cells expressing EGFP under the control of an IE2-ind...

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Published in: Cell Chemical Biology
ISSN: 2451-9456
Published: Elsevier BV 2016
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URI: https://cronfa.swan.ac.uk/Record/cronfa57648
first_indexed 2021-09-20T08:44:11Z
last_indexed 2021-09-21T03:21:11Z
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spelling 2021-09-20T10:01:46.9703309 v2 57648 2021-08-18 Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication 8d6b68ac6d8a7ab60eb04cae67116565 0000-0003-3227-1537 Giulio Nannetti Giulio Nannetti true false 2021-08-18 MEDS New targets for antiviral strategies are needed against human cytomegalovirus (HCMV), a major human pathogen. A cell-based screen aimed at finding inhibitors of the viral transcription factor Immediate-Early 2 (IE2) was performed in HCMV-infected cells expressing EGFP under the control of an IE2-inducible viral promoter. Screening of a library of bioactive small molecules led to the identification of several compounds able to inhibit EGFP expression and also HCMV replication with potency in the low-micromolar range. Follow-up studies with four selected hits indicated that they all block viral DNA synthesis as well as viral Early and Late gene expression. Furthermore, mechanistic studies confirmed that the compounds specifically act via inhibition of IE2 transactivating activity, thus blocking viral Early gene expression and the progression of virus replication. These results provide proof of concept for identifying small molecules that modulate the activity of a microbial transcription factor to control pathogen replication. Journal Article Cell Chemical Biology 23 3 340 351 Elsevier BV 2451-9456 17 3 2016 2016-03-17 10.1016/j.chembiol.2015.12.012 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 2021-09-20T10:01:46.9703309 2021-08-18T13:40:16.3443408 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Beatrice Mercorelli 1 Anna Luganini 2 Giulio Nannetti 0000-0003-3227-1537 3 Oriana Tabarrini 4 Giorgio Palù 5 Giorgio Gribaudo 6 Arianna Loregian 7
title Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication
spellingShingle Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication
Giulio Nannetti
title_short Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication
title_full Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication
title_fullStr Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication
title_full_unstemmed Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication
title_sort Drug Repurposing Approach Identifies Inhibitors of the Prototypic Viral Transcription Factor IE2 that Block Human Cytomegalovirus Replication
author_id_str_mv 8d6b68ac6d8a7ab60eb04cae67116565
author_id_fullname_str_mv 8d6b68ac6d8a7ab60eb04cae67116565_***_Giulio Nannetti
author Giulio Nannetti
author2 Beatrice Mercorelli
Anna Luganini
Giulio Nannetti
Oriana Tabarrini
Giorgio Palù
Giorgio Gribaudo
Arianna Loregian
format Journal article
container_title Cell Chemical Biology
container_volume 23
container_issue 3
container_start_page 340
publishDate 2016
institution Swansea University
issn 2451-9456
doi_str_mv 10.1016/j.chembiol.2015.12.012
publisher Elsevier BV
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
active_str 0
description New targets for antiviral strategies are needed against human cytomegalovirus (HCMV), a major human pathogen. A cell-based screen aimed at finding inhibitors of the viral transcription factor Immediate-Early 2 (IE2) was performed in HCMV-infected cells expressing EGFP under the control of an IE2-inducible viral promoter. Screening of a library of bioactive small molecules led to the identification of several compounds able to inhibit EGFP expression and also HCMV replication with potency in the low-micromolar range. Follow-up studies with four selected hits indicated that they all block viral DNA synthesis as well as viral Early and Late gene expression. Furthermore, mechanistic studies confirmed that the compounds specifically act via inhibition of IE2 transactivating activity, thus blocking viral Early gene expression and the progression of virus replication. These results provide proof of concept for identifying small molecules that modulate the activity of a microbial transcription factor to control pathogen replication.
published_date 2016-03-17T08:04:05Z
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score 11.054791

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