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Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses

RNA viruses continue to remain a clear and present threat for potential pandemics due to their rapid evolution. To mitigate their impact, we urgently require antiviral agents that can inhibit multiple families of disease-causing viruses, such as arthropod-borne and respiratory pathogens. Potentiatin...

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Autores principales: Garcia, Gustavo, Irudayam, Joseph Ignatius, Jeyachandran, Arjit Vijay, Dubey, Swati, Chang, Christina, Cario, Sebastian Castillo, Price, Nate, Arumugam, Sathya, Marquez, Angelica L., Shah, Aayushi, Fanaei, Amir, Chakravarty, Nikhil, Joshi, Shantanu, Sinha, Sanjeev, French, Samuel W., Parcells, Mark, Ramaiah, Arunachalam, Arumugaswami, Vaithilingaraja
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882367/
https://www.ncbi.nlm.nih.gov/pubmed/36711787
http://dx.doi.org/10.1101/2023.01.19.524824
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author Garcia, Gustavo
Irudayam, Joseph Ignatius
Jeyachandran, Arjit Vijay
Dubey, Swati
Chang, Christina
Cario, Sebastian Castillo
Price, Nate
Arumugam, Sathya
Marquez, Angelica L.
Shah, Aayushi
Fanaei, Amir
Chakravarty, Nikhil
Joshi, Shantanu
Sinha, Sanjeev
French, Samuel W.
Parcells, Mark
Ramaiah, Arunachalam
Arumugaswami, Vaithilingaraja
author_facet Garcia, Gustavo
Irudayam, Joseph Ignatius
Jeyachandran, Arjit Vijay
Dubey, Swati
Chang, Christina
Cario, Sebastian Castillo
Price, Nate
Arumugam, Sathya
Marquez, Angelica L.
Shah, Aayushi
Fanaei, Amir
Chakravarty, Nikhil
Joshi, Shantanu
Sinha, Sanjeev
French, Samuel W.
Parcells, Mark
Ramaiah, Arunachalam
Arumugaswami, Vaithilingaraja
author_sort Garcia, Gustavo
collection PubMed
description RNA viruses continue to remain a clear and present threat for potential pandemics due to their rapid evolution. To mitigate their impact, we urgently require antiviral agents that can inhibit multiple families of disease-causing viruses, such as arthropod-borne and respiratory pathogens. Potentiating host antiviral pathways can prevent or limit viral infections before escalating into a major outbreak. Therefore, it is critical to identify broad-spectrum antiviral agents. We have tested a small library of innate immune agonists targeting pathogen recognition receptors, including TLRs, STING, NOD, Dectin and cytosolic DNA or RNA sensors. We observed that TLR3, STING, TLR8 and Dectin-1 ligands inhibited arboviruses, Chikungunya virus (CHIKV), West Nile virus (WNV) and Zika virus, to varying degrees. Cyclic dinucleotide (CDN) STING agonists, such as cAIMP, diABZI, and 2’,3’-cGAMP, and Dectin-1 agonist scleroglucan, demonstrated the most potent, broad-spectrum antiviral function. Comparative transcriptome analysis revealed that CHIKV-infected cells had larger number of differentially expressed genes than of WNV and ZIKV. Furthermore, gene expression analysis showed that cAIMP treatment rescued cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provided protection against CHIKV in a CHIKV-arthritis mouse model. Cardioprotective effects of synthetic STING ligands against CHIKV, WNV, SARS-CoV-2 and enterovirus D68 (EV-D68) infections were demonstrated using human cardiomyocytes. Interestingly, the direct-acting antiviral drug remdesivir, a nucleoside analogue, was not effective against CHIKV and WNV, but exhibited potent antiviral effects against SARS-CoV-2, RSV (respiratory syncytial virus), and EV-D68. Our study identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses, which can be rapidly deployed to prevent or mitigate future pandemics.
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spelling pubmed-98823672023-01-28 Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses Garcia, Gustavo Irudayam, Joseph Ignatius Jeyachandran, Arjit Vijay Dubey, Swati Chang, Christina Cario, Sebastian Castillo Price, Nate Arumugam, Sathya Marquez, Angelica L. Shah, Aayushi Fanaei, Amir Chakravarty, Nikhil Joshi, Shantanu Sinha, Sanjeev French, Samuel W. Parcells, Mark Ramaiah, Arunachalam Arumugaswami, Vaithilingaraja bioRxiv Article RNA viruses continue to remain a clear and present threat for potential pandemics due to their rapid evolution. To mitigate their impact, we urgently require antiviral agents that can inhibit multiple families of disease-causing viruses, such as arthropod-borne and respiratory pathogens. Potentiating host antiviral pathways can prevent or limit viral infections before escalating into a major outbreak. Therefore, it is critical to identify broad-spectrum antiviral agents. We have tested a small library of innate immune agonists targeting pathogen recognition receptors, including TLRs, STING, NOD, Dectin and cytosolic DNA or RNA sensors. We observed that TLR3, STING, TLR8 and Dectin-1 ligands inhibited arboviruses, Chikungunya virus (CHIKV), West Nile virus (WNV) and Zika virus, to varying degrees. Cyclic dinucleotide (CDN) STING agonists, such as cAIMP, diABZI, and 2’,3’-cGAMP, and Dectin-1 agonist scleroglucan, demonstrated the most potent, broad-spectrum antiviral function. Comparative transcriptome analysis revealed that CHIKV-infected cells had larger number of differentially expressed genes than of WNV and ZIKV. Furthermore, gene expression analysis showed that cAIMP treatment rescued cells from CHIKV-induced dysregulation of cell repair, immune, and metabolic pathways. In addition, cAIMP provided protection against CHIKV in a CHIKV-arthritis mouse model. Cardioprotective effects of synthetic STING ligands against CHIKV, WNV, SARS-CoV-2 and enterovirus D68 (EV-D68) infections were demonstrated using human cardiomyocytes. Interestingly, the direct-acting antiviral drug remdesivir, a nucleoside analogue, was not effective against CHIKV and WNV, but exhibited potent antiviral effects against SARS-CoV-2, RSV (respiratory syncytial virus), and EV-D68. Our study identifies broad-spectrum antivirals effective against multiple families of pandemic potential RNA viruses, which can be rapidly deployed to prevent or mitigate future pandemics. Cold Spring Harbor Laboratory 2023-01-20 /pmc/articles/PMC9882367/ /pubmed/36711787 http://dx.doi.org/10.1101/2023.01.19.524824 Text en https://creativecommons.org/licenses/by-nc-nd/4.0/This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
spellingShingle Article
Garcia, Gustavo
Irudayam, Joseph Ignatius
Jeyachandran, Arjit Vijay
Dubey, Swati
Chang, Christina
Cario, Sebastian Castillo
Price, Nate
Arumugam, Sathya
Marquez, Angelica L.
Shah, Aayushi
Fanaei, Amir
Chakravarty, Nikhil
Joshi, Shantanu
Sinha, Sanjeev
French, Samuel W.
Parcells, Mark
Ramaiah, Arunachalam
Arumugaswami, Vaithilingaraja
Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses
title Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses
title_full Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses
title_fullStr Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses
title_full_unstemmed Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses
title_short Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses
title_sort broad-spectrum antiviral inhibitors targeting pandemic potential rna viruses
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9882367/
https://www.ncbi.nlm.nih.gov/pubmed/36711787
http://dx.doi.org/10.1101/2023.01.19.524824
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