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bioRxiv · 10.1101/2023.01.19.524824

Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses

Garcia, G.·Ignatius Irudayam, J.·Vijay Jeyachandran, A.·Dubey, S.·Chang, C.·Castillo Cario, S.·Price, N.·Arumugam, S.·Marquez, A. L.·Shah, A.·Fanaei, A.·Chakravarty, N.·Joshi, S.·Sinha, S.·French, S. W.·Parcells, M.·Ramaiah, A.·Arumugaswami, V.
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Abstract

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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Garcia, G., Ignatius Irudayam, J., Vijay Jeyachandran, A., Dubey, S., Chang, C., Castillo Cario, S., Price, N., Arumugam, S., Marquez, A. L., Shah, A., Fanaei, A., Chakravarty, N., Joshi, S., Sinha, S., French, S. W., Parcells, M., Ramaiah, A., Arumugaswami, V.. 2023-01-20. Broad-spectrum antiviral inhibitors targeting pandemic potential RNA viruses. https://doi.org/10.1101/2023.01.19.524824

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