Polyphenolic promiscuity, inflammation-coupled selectivity: 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 frequently consumed in the diet in herbs, spices, fruits and vegetables. Examining plant secondary metabolites, we review recent elucidations into the pharmacological activity of flavonoids and other polyphenolic compounds and also survey their putative frequent-hitter behavior. Polyphenols, like many drugs, are glucuronidated post-ingestion. In an inflammatory milieu such as infection, a reversion back to the active aglycone by the release of β-glucuronidase from neutrophils and macrophages allows cellular entry of the aglycone. In the context of viral infection, virions and intracellular virus particles may be exposed to promiscuous binding by the polyphenol aglycones resulting in viral inhibition. As the mechanism's scope would apply to the diverse range of virus species that elicit inflammation in infected hosts, we highlight pre-clinical studies of polyphenol aglycones, such as luteolin, isoginkgetin, quercetin, quercetagetin, baicalein, curcumin, fisetin and hesperetin that reduce virion replication spanning multiple distinct virus genera. It is hoped that greater awareness of the potential spatial selectivity of polyphenolic activation to sites of pathogenic infection will spur renewed research and clinical attention for natural products antiviral assaying and trialing over a wide array of infectious viral diseases.