Identification of natural products targeting human herpesvirus DNA polymerase as antiviral lead

Infectious herpesviruses are implicated in a broad spectrum of human disorders, from mild cold sores to severe encephalitis and cancers. To combat herpesvirus infections, natural products should be a rich source of potential drug leads. However, natural products have long been bothered by discovering the protein target. In this study, we reviewed the studies on identifying natural products with anti-herpetic activity and collected the compound information. A compound library was constructed using these compounds and used for virtual screening together with structural models of human herpesvirus DNA polymerases. Then, candidate compounds were chosen and subjected to further activity measurement. Consequently, five compounds with moderate-to-high inhibitory activity against three herpesvirus DNA polymerases were identified. These compounds represented potential pan-antiviral lead compounds targeting the known druggable DNA polymerases. Furthermore, binding of four of the five compounds was independent on the binding of DNA duplex, unlike the behavior of traditional non-nucleoside inhibitors, revealing novel inhibitory mechanism of these natural products.