Cargando…
Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses
Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approa...
Autores principales: | , , , , , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762994/ https://www.ncbi.nlm.nih.gov/pubmed/33322045 http://dx.doi.org/10.3390/v12121423 |
_version_ | 1783627911807369216 |
---|---|
author | Tampere, Marianna Pettke, Aleksandra Salata, Cristiano Wallner, Olov Koolmeister, Tobias Cazares-Körner, Armando Visnes, Torkild Hesselman, Maria Carmen Kunold, Elena Wiita, Elisee Kalderén, Christina Lightowler, Molly Jemth, Ann-Sofie Lehtiö, Janne Rosenquist, Åsa Warpman-Berglund, Ulrika Helleday, Thomas Mirazimi, Ali Jafari, Rozbeh Puumalainen, Marjo-Riitta |
author_facet | Tampere, Marianna Pettke, Aleksandra Salata, Cristiano Wallner, Olov Koolmeister, Tobias Cazares-Körner, Armando Visnes, Torkild Hesselman, Maria Carmen Kunold, Elena Wiita, Elisee Kalderén, Christina Lightowler, Molly Jemth, Ann-Sofie Lehtiö, Janne Rosenquist, Åsa Warpman-Berglund, Ulrika Helleday, Thomas Mirazimi, Ali Jafari, Rozbeh Puumalainen, Marjo-Riitta |
author_sort | Tampere, Marianna |
collection | PubMed |
description | Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies. |
format | Online Article Text |
id | pubmed-7762994 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-77629942020-12-27 Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses Tampere, Marianna Pettke, Aleksandra Salata, Cristiano Wallner, Olov Koolmeister, Tobias Cazares-Körner, Armando Visnes, Torkild Hesselman, Maria Carmen Kunold, Elena Wiita, Elisee Kalderén, Christina Lightowler, Molly Jemth, Ann-Sofie Lehtiö, Janne Rosenquist, Åsa Warpman-Berglund, Ulrika Helleday, Thomas Mirazimi, Ali Jafari, Rozbeh Puumalainen, Marjo-Riitta Viruses Article Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies. MDPI 2020-12-10 /pmc/articles/PMC7762994/ /pubmed/33322045 http://dx.doi.org/10.3390/v12121423 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Tampere, Marianna Pettke, Aleksandra Salata, Cristiano Wallner, Olov Koolmeister, Tobias Cazares-Körner, Armando Visnes, Torkild Hesselman, Maria Carmen Kunold, Elena Wiita, Elisee Kalderén, Christina Lightowler, Molly Jemth, Ann-Sofie Lehtiö, Janne Rosenquist, Åsa Warpman-Berglund, Ulrika Helleday, Thomas Mirazimi, Ali Jafari, Rozbeh Puumalainen, Marjo-Riitta Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses |
title | Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses |
title_full | Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses |
title_fullStr | Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses |
title_full_unstemmed | Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses |
title_short | Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses |
title_sort | novel broad-spectrum antiviral inhibitors targeting host factors essential for replication of pathogenic rna viruses |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762994/ https://www.ncbi.nlm.nih.gov/pubmed/33322045 http://dx.doi.org/10.3390/v12121423 |
work_keys_str_mv | AT tamperemarianna novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT pettkealeksandra novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT salatacristiano novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT wallnerolov novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT koolmeistertobias novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT cazareskornerarmando novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT visnestorkild novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT hesselmanmariacarmen novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT kunoldelena novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT wiitaelisee novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT kalderenchristina novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT lightowlermolly novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT jemthannsofie novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT lehtiojanne novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT rosenquistasa novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT warpmanberglundulrika novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT helledaythomas novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT mirazimiali novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT jafarirozbeh novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses AT puumalainenmarjoriitta novelbroadspectrumantiviralinhibitorstargetinghostfactorsessentialforreplicationofpathogenicrnaviruses |