Herpes simplex virus 1 (HSV-1) is a common human pathogen that causes lifelong
latent infection of sensory neurons. Non-
nucleoside inhibitors that can limit HSV-1 recurrence are particularly useful in treating immunocompromised individuals or cases of emerging
acyclovir-resistant strains of herpesvirus. We report that
chebulagic acid (CHLA) and
punicalagin (PUG), two
hydrolyzable tannins isolated from the dried fruits of Terminalia chebula Retz. (Combretaceae), inhibit HSV-1 entry at noncytotoxic doses in A549 human lung cells. Experiments revealed that both
tannins targeted and inactivated HSV-1 viral particles and could prevent binding, penetration, and cell-to-cell spread, as well as
secondary infection. The
antiviral effect from either of the
tannins was not associated with induction of
type I interferon-mediated responses, nor was pretreatment of the host cell protective against HSV-1. Their inhibitory activities targeted HSV-1
glycoproteins since both natural compounds were able to block polykaryocyte formation mediated by expression of recombinant viral
glycoproteins involved in attachment and membrane fusion. Our results indicated that CHLA and PUG blocked interactions between cell surface
glycosaminoglycans and HSV-1
glycoproteins. Furthermore, the
antiviral activities from the two
tannins were significantly diminished in mutant cell lines unable to produce
heparan sulfate and
chondroitin sulfate and could be rescued upon reconstitution of
heparan sulfate biosynthesis. We suggest that the
hydrolyzable tannins CHLA and PUG may be useful as competitors for
glycosaminoglycans in the management of HSV-1
infections and that they may help reduce the risk for development of viral drug resistance during
therapy with
nucleoside analogues.