A Pyrido‐Quinoxaline Derivative That Downregulates Reticulon 3 Protein Exhibits Potent Antiviral Activity Against Zika Virus

In the wake of the COVID-19 pandemic, awareness of emerging pathogens has significantly increased, prompting greater investment in research and preparedness. In this context, arboviral diseases are recognized as unmet medical challenges due to their rapid spread. Notably, the geographical range of several flaviviral diseases is expanding: Zika virus (ZIKV), a member of the Flaviviridae family, has recently been linked to outbreaks associated with a rise in microcephaly cases in tropical regions. To contribute to the development of novel antiviral therapies, evaluation of a set of compounds with an antiviral activity against ZIKV was carried out. These compounds were originally identified as inhibitors of bovine viral diarrhea virus, another member of the Flaviviridae family. Two related compounds turned out to be active against ZIKV. One emerged as a particularly strong antiviral candidate, demonstrating high efficacy in inhibiting ZIKV replication, and became the focus of this study. Its activity was tested against a number of viruses of human health relevance and the compound was found to be effective against a number of viruses that use the endoplasmic reticulum as a replication hub. Indeed, we found that the Reticulon 3 protein is potently downregulated in the presence of the compound, whereas other endoplasmic reticulum-resident proteins are not affected. Because Reticulon 3 has a role in the replication of positive-sense single-stranded RNA viruses, an indirect antiviral effect of the compound studied was hypothesized. This compound may be considered as a promising lead for further studies aimed at the development of broad-spectrum antiviral drugs.