Sumac Polyphenols as Pan-Herpesvirus Inhibitors

Pandemic preparedness is a complex of threat-agnostic countermeasures developed in advance which would be efficient against a future outbreak regardless of its causative agent, and broad-spectrum antivirals constitute a critical component of this complex. Plant polyphenols are known to suppress viruses of unrelated families by acting on multiple viral and cellular structures. We therefore searched for broad-spectrum antivirals among polyphenols that have been confirmed as safe to humans. The ellagitannin geraniin and galloylglucose constituents of the drug Rutan (1,2,3,4,6-penta-O-galloyl-β-D-glucose [R5], 3-bis-O-galloyl-1,2,4,6-tetra-O-galloyl-β-D-glucose [R6], 2,4-bis-O-galloyl-1,3,6-tri-O-galloyl-β-D-glucose [R7], 2,3,4-bis-O-galloyl-1,6-di-O-galloyl-β-D-glucose [R8]) were isolated from <i>Geranium sanguineum</i> and sumac (<i>Rhus coriaria</i>), respectively. We revealed their activity towards herpes simplex viruses (HSV-1 and HSV-2), human cytomegalovirus (CMV), and the Epstein-Barr virus (EBV). R5 suppressed HSV-1 and HSV-2 with equal efficiency, while Rutan and R7 were more active against HSV-1, and geraniin against HSV-2. Rutan and R5 also inhibited the intracellular replication of CMV and EBV (contrary to our expectations, geraniin and polyphenols R6-R8 showed no activity). Thus, we have shown for the first time that sumac polyphenols are capable of suppressing-in addition to HIV, influenza virus, and SARS-CoV-2-the reproduction of representatives of all three Orthoherpesviridae subfamilies, meeting the criteria for further development as broad-spectrum antivirals.