The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation
Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-12-01
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| Series: | Viruses |
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| Online Access: | https://www.mdpi.com/1999-4915/14/1/60 |
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| author | Subha Dahal Ran Cheng Peter K. Cheung Terek Been Ramy Malty Melissa Geng Sarah Manianis Lulzim Shkreta Shahrazad Jahanshahi Johanne Toutant Rose Chan Sean Park Mark A. Brockman Mohan Babu Samira Mubareka Karen Mossman Arinjay Banerjee Scott Gray-Owen Martha Brown Walid A. Houry Benoit Chabot David Grierson Alan Cochrane |
| author_facet | Subha Dahal Ran Cheng Peter K. Cheung Terek Been Ramy Malty Melissa Geng Sarah Manianis Lulzim Shkreta Shahrazad Jahanshahi Johanne Toutant Rose Chan Sean Park Mark A. Brockman Mohan Babu Samira Mubareka Karen Mossman Arinjay Banerjee Scott Gray-Owen Martha Brown Walid A. Houry Benoit Chabot David Grierson Alan Cochrane |
| author_sort | Subha Dahal |
| collection | DOAJ |
| description | Medicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC<sub>50</sub> ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability. |
| first_indexed | 2024-03-10T00:21:29Z |
| format | Article |
| id | doaj.art-1c76f49ace8b4a22bb54cfbd594bd88c |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T00:21:29Z |
| publishDate | 2021-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-1c76f49ace8b4a22bb54cfbd594bd88c2023-11-23T15:41:32ZengMDPI AGViruses1999-49152021-12-011416010.3390/v14010060The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/AccumulationSubha Dahal0Ran Cheng1Peter K. Cheung2Terek Been3Ramy Malty4Melissa Geng5Sarah Manianis6Lulzim Shkreta7Shahrazad Jahanshahi8Johanne Toutant9Rose Chan10Sean Park11Mark A. Brockman12Mohan Babu13Samira Mubareka14Karen Mossman15Arinjay Banerjee16Scott Gray-Owen17Martha Brown18Walid A. Houry19Benoit Chabot20David Grierson21Alan Cochrane22Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Biochemistry, 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 Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaBritish Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, CanadaResearch and Innovation Centre, Department of Biochemistry, University of Regina, Regina, SK S4S 0A2, CanadaDepartment of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Medicine, McMaster University, Hamilton, ON L8N 3Z5, CanadaDepartment of Medicine, McMaster University, Hamilton, ON L8N 3Z5, 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, University of Toronto, Toronto, ON M5S 1A8, CanadaDepartment of Microbiology and Infectious Diseases, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, CanadaFaculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC V6T 1Z3, CanadaDepartment of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, CanadaMedicinal chemistry optimization of a previously described stilbene inhibitor of HIV-1, 5350150 (2-(2-(5-nitro-2-thienyl)vinyl)quinoline), led to the identification of the thiazole-5-carboxamide derivative (GPS491), which retained potent anti-HIV-1 activity with reduced toxicity. In this report, we demonstrate that the block of HIV-1 replication by GPS491 is accompanied by a drastic inhibition of viral gene expression (IC<sub>50</sub> ~ 0.25 µM), and alterations in the production of unspliced, singly spliced, and multiply spliced HIV-1 RNAs. GPS491 also inhibited the replication of adenovirus and multiple coronaviruses. Low µM doses of GPS491 reduced adenovirus infectious yield ~1000 fold, altered virus early gene expression/viral E1A RNA processing, blocked viral DNA amplification, and inhibited late (hexon) gene expression. Loss of replication of multiple coronaviruses (229E, OC43, SARS-CoV2) upon GPS491 addition was associated with the inhibition of viral structural protein expression and the formation of virus particles. Consistent with the observed changes in viral RNA processing, GPS491 treatment induced selective alterations in the accumulation/phosphorylation/function of splicing regulatory SR proteins. Our study establishes that a compound that impacts the activity of cellular factors involved in RNA processing can prevent the replication of several viruses with minimal effect on cell viability.https://www.mdpi.com/1999-4915/14/1/60HIV-1adenoviruscoronavirusRNA processinginhibitor |
| spellingShingle | Subha Dahal Ran Cheng Peter K. Cheung Terek Been Ramy Malty Melissa Geng Sarah Manianis Lulzim Shkreta Shahrazad Jahanshahi Johanne Toutant Rose Chan Sean Park Mark A. Brockman Mohan Babu Samira Mubareka Karen Mossman Arinjay Banerjee Scott Gray-Owen Martha Brown Walid A. Houry Benoit Chabot David Grierson Alan Cochrane The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation Viruses HIV-1 adenovirus coronavirus RNA processing inhibitor |
| title | The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation |
| title_full | The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation |
| title_fullStr | The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation |
| title_full_unstemmed | The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation |
| title_short | The Thiazole-5-Carboxamide GPS491 Inhibits HIV-1, Adenovirus, and Coronavirus Replication by Altering RNA Processing/Accumulation |
| title_sort | thiazole 5 carboxamide gps491 inhibits hiv 1 adenovirus and coronavirus replication by altering rna processing accumulation |
| topic | HIV-1 adenovirus coronavirus RNA processing inhibitor |
| url | https://www.mdpi.com/1999-4915/14/1/60 |
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