Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals
Treatment options for viral infections are limited and viruses have proven adept at evolving resistance to many existing therapies, highlighting a significant vulnerability in our defenses. In response to this challenge, we explored the modulation of cellular RNA metabolic processes as an alternativ...
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2024-12-01
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| Online Access: | https://www.mdpi.com/1999-4915/17/1/54 |
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| author | Ali Zahedi Amiri Choudhary Ahmed Subha Dahal Filomena Grosso Haomin Leng Peter Stoilov Maria Mangos Johanne Toutant Lulzim Shkreta Liliana Attisano Benoit Chabot Martha Brown Mario Huesca Alan Cochrane |
| author_facet | Ali Zahedi Amiri Choudhary Ahmed Subha Dahal Filomena Grosso Haomin Leng Peter Stoilov Maria Mangos Johanne Toutant Lulzim Shkreta Liliana Attisano Benoit Chabot Martha Brown Mario Huesca Alan Cochrane |
| author_sort | Ali Zahedi Amiri |
| collection | DOAJ |
| description | Treatment options for viral infections are limited and viruses have proven adept at evolving resistance to many existing therapies, highlighting a significant vulnerability in our defenses. In response to this challenge, we explored the modulation of cellular RNA metabolic processes as an alternative paradigm to antiviral development. Previously, the small molecule 5342191 was identified as a potent inhibitor of HIV-1 replication by altering viral RNA accumulation at doses that minimally affect host gene expression. In this report, we document 5342191 as a potent inhibitor of adenovirus, coronavirus, and influenza replication. In each case, 5342191-mediated reduction in virus replication was associated with altered viral RNA accumulation and loss of viral structural protein expression. Interestingly, while resistant viruses were rapidly isolated for compounds targeting either virus-encoded proteases or polymerases, we have not yet isolated 5342191-resistant variants of coronavirus or influenza. As with HIV-1, 5342191’s inhibition of coronaviruses and influenza is mediated through the activation of specific cell signaling networks, including GPCR and/or MAPK signaling pathways that ultimately affect SR kinase expression. Together, these studies highlight the therapeutic potential of compounds that target cellular processes essential for the replication of multiple viruses. Not only do these compounds hold promise as broad-spectrum antivirals, but they also offer the potential of greater resilience in combating viral infections. |
| format | Article |
| id | doaj-art-8b16f3478d8348b7a751fdd7a2c0b5d3 |
| institution | Kabale University |
| issn | 1999-4915 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj-art-8b16f3478d8348b7a751fdd7a2c0b5d32025-01-24T13:52:25ZengMDPI AGViruses1999-49152024-12-011715410.3390/v17010054Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel AntiviralsAli Zahedi Amiri0Choudhary Ahmed1Subha Dahal2Filomena Grosso3Haomin Leng4Peter Stoilov5Maria Mangos6Johanne Toutant7Lulzim Shkreta8Liliana Attisano9Benoit Chabot10Martha Brown11Mario Huesca12Alan Cochrane13Virocarb Inc., Toronto, ON M8V 3Y3, CanadaVirocarb Inc., Toronto, ON M8V 3Y3, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Biochemistry and Molecular Medicine, West Virginia University, Morgantown, WV 26506, USADepartment of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, CanadaDepartment of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, CanadaDepartment of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Microbiology and Infectious Diseases, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaVirocarb Inc., Toronto, ON M8V 3Y3, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaTreatment options for viral infections are limited and viruses have proven adept at evolving resistance to many existing therapies, highlighting a significant vulnerability in our defenses. In response to this challenge, we explored the modulation of cellular RNA metabolic processes as an alternative paradigm to antiviral development. Previously, the small molecule 5342191 was identified as a potent inhibitor of HIV-1 replication by altering viral RNA accumulation at doses that minimally affect host gene expression. In this report, we document 5342191 as a potent inhibitor of adenovirus, coronavirus, and influenza replication. In each case, 5342191-mediated reduction in virus replication was associated with altered viral RNA accumulation and loss of viral structural protein expression. Interestingly, while resistant viruses were rapidly isolated for compounds targeting either virus-encoded proteases or polymerases, we have not yet isolated 5342191-resistant variants of coronavirus or influenza. As with HIV-1, 5342191’s inhibition of coronaviruses and influenza is mediated through the activation of specific cell signaling networks, including GPCR and/or MAPK signaling pathways that ultimately affect SR kinase expression. Together, these studies highlight the therapeutic potential of compounds that target cellular processes essential for the replication of multiple viruses. Not only do these compounds hold promise as broad-spectrum antivirals, but they also offer the potential of greater resilience in combating viral infections.https://www.mdpi.com/1999-4915/17/1/54broad-spectrum antiviralRNA processingadenoviruscoronavirusinfluenza |
| spellingShingle | Ali Zahedi Amiri Choudhary Ahmed Subha Dahal Filomena Grosso Haomin Leng Peter Stoilov Maria Mangos Johanne Toutant Lulzim Shkreta Liliana Attisano Benoit Chabot Martha Brown Mario Huesca Alan Cochrane Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals Viruses broad-spectrum antiviral RNA processing adenovirus coronavirus influenza |
| title | Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals |
| title_full | Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals |
| title_fullStr | Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals |
| title_full_unstemmed | Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals |
| title_short | Exploiting the Achilles’ Heel of Viral RNA Processing to Develop Novel Antivirals |
| title_sort | exploiting the achilles heel of viral rna processing to develop novel antivirals |
| topic | broad-spectrum antiviral RNA processing adenovirus coronavirus influenza |
| url | https://www.mdpi.com/1999-4915/17/1/54 |
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