Ellagitannins as synergists of ACV on the replication of ACV-resistant strains of HSV 1 and 2

- Ellagitannins castalagin, vescalagin and grandinin showed strong inhibition of the replication of HSV ACV-resistant strains.
- Macroplaque reduction assay and two representative cytopathic effect inhibition assays in MDBK cells were used.
- The effect of the combination of ellagitannins and ACV on HSV ACV-resistant strains manifested a marked synergistic effect.
- The combination of the ellagitannin(s) and ACV resulted in no toxicity to the cells at the tested concentrations.
- The results gathered demonstrate the highly promising potential of these plant polyphenols as antiherpetic agents.

The plant-derived polyphenolic compounds castalagin, vescalagin and grandinin (C-glucosidic ellagitannins containing nonahydroxyterphenoyl) manifested a strong inhibitory effect on the replication of acyclovir-resistant strains of herpes simplex viruses (HSV) type 1 and 2 in MDBK cells in focus forming units (i.e., microscopically registered microplaques) reduction assay and in two variants of cytopathic effect inhibition test. The effect on the acyclovir (ACV)-resistant herpes simplex virus type 1 (HSV-1) strain was markedly higher compared to that on the ACV-resistant herpes simplex virus type 2 (HSV-2). The three compounds showed comparable levels of antiviral activity against ACV-resistant HSV strains, in contrast with previous results where castalagin exerted the highest degree of activity against wild type HSV strains (Vilhelmova et al., 2011). Combinations of ellagitannins and ACV were tested on the ACV-resistant strains of both HSV-1 and 2 and produced synergistic effects that were revealed by applying the three-dimensional approach of Prichard and Shipman (1990). The ellagitannin(s)-ACV combination applied against ACV-resistant HSV-1 produced a much stronger synergistic effect compared to the effect observed against ACV-resistant HSV-2. The study of the effects of the combination ellagitannin(s)-ACF on intact cell monolayers did not show any toxicity resulting from interaction between the two substances. Altogether, the results obtained in this study demonstrate the highly promising potential of these plant polyphenols as antiherpetic agents.