Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies
Abstract The COVID-19 pandemic has created a global health crisis, with challenges arising from the ongoing evolution of the SARS-CoV-2 virus, the emergence of new strains, and the long-term effects of COVID-19. Aiming to overcome the development of viral resistance, our study here focused on develo...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-11-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07143-z |
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| author | Yu-Qian Mao Shahrzad Jahanshahi Ramy Malty David A. J. Van Ommen Yimei Wan Trevor M. Morey Stephanie H. W. Chuang Veronika Pavlova Choudhary Ahmed Subha Dahal Funing Lin Maria Mangos Jocelyn Nurtanto Yuetong Song Terek Been Natasha Christie-Holmes Scott D. Gray-Owen Mohan Babu Amy P. Wong Robert A. Batey Liliana Attisano Alan Cochrane Walid A. Houry |
| author_facet | Yu-Qian Mao Shahrzad Jahanshahi Ramy Malty David A. J. Van Ommen Yimei Wan Trevor M. Morey Stephanie H. W. Chuang Veronika Pavlova Choudhary Ahmed Subha Dahal Funing Lin Maria Mangos Jocelyn Nurtanto Yuetong Song Terek Been Natasha Christie-Holmes Scott D. Gray-Owen Mohan Babu Amy P. Wong Robert A. Batey Liliana Attisano Alan Cochrane Walid A. Houry |
| author_sort | Yu-Qian Mao |
| collection | DOAJ |
| description | Abstract The COVID-19 pandemic has created a global health crisis, with challenges arising from the ongoing evolution of the SARS-CoV-2 virus, the emergence of new strains, and the long-term effects of COVID-19. Aiming to overcome the development of viral resistance, our study here focused on developing broad-spectrum pan-coronavirus antiviral therapies by targeting host protein quality control mechanisms essential for viral replication. Screening an in-house compound library led to the discovery of three candidate compounds targeting cellular proteostasis. The three compounds are (1) the nucleotide analog cordycepin, (2) a benzothiozole analog, and (3) an acyldepsipeptide analog initially developed as part of a campaign to target the mitochondrial ClpP protease. These compounds demonstrated dose-dependent efficacy against multiple coronaviruses, including SARS-CoV-2, effectively inhibiting viral replication in vitro as well as in lung organoids. Notably, the compounds also showed efficacy against SARS-CoV-2 delta and omicron strains. As part of this work, we developed a BSL2-level cell-integrated SARS-CoV-2 replicon, which could serve as a valuable tool for high-throughput screening and studying intracellular viral replication. Our study should aid in the advancement of antiviral drug development efforts. |
| format | Article |
| id | doaj-art-34c783c190b4473fa3becce3ef2a2d68 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-34c783c190b4473fa3becce3ef2a2d682024-11-10T12:39:09ZengNature PortfolioCommunications Biology2399-36422024-11-017111910.1038/s42003-024-07143-zTargeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapiesYu-Qian Mao0Shahrzad Jahanshahi1Ramy Malty2David A. J. Van Ommen3Yimei Wan4Trevor M. Morey5Stephanie H. W. Chuang6Veronika Pavlova7Choudhary Ahmed8Subha Dahal9Funing Lin10Maria Mangos11Jocelyn Nurtanto12Yuetong Song13Terek Been14Natasha Christie-Holmes15Scott D. Gray-Owen16Mohan Babu17Amy P. Wong18Robert A. Batey19Liliana Attisano20Alan Cochrane21Walid A. Houry22Department of Biochemistry, University of TorontoDepartment of Biochemistry, University of TorontoDepartment of Biochemistry, University of TorontoDepartment of Biochemistry, University of TorontoDepartment of Biochemistry, University of TorontoDepartment of Biochemistry, University of TorontoDepartment of Biochemistry, University of TorontoDepartment of Biochemistry, University of TorontoDepartment of Molecular Genetics, University of TorontoDepartment of Molecular Genetics, University of TorontoDepartment of Chemistry, University of TorontoDonnelly Centre, University of TorontoDonnelly Centre, University of TorontoProgram in Developmental and Stem Cell Biology, Hospital for Sick ChildrenDepartment of Molecular Genetics, University of TorontoToronto High Containment Facility, Temerty Faculty of Medicine, University of TorontoDepartment of Molecular Genetics, University of TorontoDepartment of Chemistry and Biochemistry, University of ReginaProgram in Developmental and Stem Cell Biology, Hospital for Sick ChildrenDepartment of Chemistry, University of TorontoDepartment of Biochemistry, University of TorontoDepartment of Molecular Genetics, University of TorontoDepartment of Biochemistry, University of TorontoAbstract The COVID-19 pandemic has created a global health crisis, with challenges arising from the ongoing evolution of the SARS-CoV-2 virus, the emergence of new strains, and the long-term effects of COVID-19. Aiming to overcome the development of viral resistance, our study here focused on developing broad-spectrum pan-coronavirus antiviral therapies by targeting host protein quality control mechanisms essential for viral replication. Screening an in-house compound library led to the discovery of three candidate compounds targeting cellular proteostasis. The three compounds are (1) the nucleotide analog cordycepin, (2) a benzothiozole analog, and (3) an acyldepsipeptide analog initially developed as part of a campaign to target the mitochondrial ClpP protease. These compounds demonstrated dose-dependent efficacy against multiple coronaviruses, including SARS-CoV-2, effectively inhibiting viral replication in vitro as well as in lung organoids. Notably, the compounds also showed efficacy against SARS-CoV-2 delta and omicron strains. As part of this work, we developed a BSL2-level cell-integrated SARS-CoV-2 replicon, which could serve as a valuable tool for high-throughput screening and studying intracellular viral replication. Our study should aid in the advancement of antiviral drug development efforts.https://doi.org/10.1038/s42003-024-07143-z |
| spellingShingle | Yu-Qian Mao Shahrzad Jahanshahi Ramy Malty David A. J. Van Ommen Yimei Wan Trevor M. Morey Stephanie H. W. Chuang Veronika Pavlova Choudhary Ahmed Subha Dahal Funing Lin Maria Mangos Jocelyn Nurtanto Yuetong Song Terek Been Natasha Christie-Holmes Scott D. Gray-Owen Mohan Babu Amy P. Wong Robert A. Batey Liliana Attisano Alan Cochrane Walid A. Houry Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies Communications Biology |
| title | Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies |
| title_full | Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies |
| title_fullStr | Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies |
| title_full_unstemmed | Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies |
| title_short | Targeting protein homeostasis with small molecules as a strategy for the development of pan-coronavirus antiviral therapies |
| title_sort | targeting protein homeostasis with small molecules as a strategy for the development of pan coronavirus antiviral therapies |
| url | https://doi.org/10.1038/s42003-024-07143-z |
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