Polyphenolic Promiscuity, Inflammation-coupled Specificity: Whether PAINs Filters Mask an Antiviral Asset

The Covid-19 pandemic has elicited much laboratory and clinical research attention on vaccines, mAbs, and certain small-molecule antivirals against SARS-CoV-2 infection. By contrast, there has been comparatively little attention on plant-derived compounds, especially those that are understood to be safely ingested at common doses and are often commonly consumed in the diet. With broader scope for assays and trials against a diverse array of viral infections, we review elucidations of the pharmacokinetic mechanisms of polyphenolic compounds over the past two decades and survey their putative frequent-hitter behavior. Many polyphenols are indeed promiscuous binders, suggesting a candidate mechanism of non-specific inhibition combined with inflammation-targeting specificity. Since such a specificity mechanism combined with promiscuity poses a possible pathway of inhibiting viral replication uniquely in infected tissue, we highlight pre-clinical studies of polyphenol aglycones that reduce virion replication. It is hoped that greater awareness of the potential specificity of polyphenolic activation to sites of pathogenic infection will spur renewed research and clinical attention on assaying and trialing against several infectious viral diseases.