Six stilbene derivatives isolated from Mulberry leaves including Kuwanon X, Mulberrofuran C, Mulberrofuran G, Moracin C, Moracin M 3′-O-b-glucopyranoside and Moracin M were found to have antiviral effects against herpes simplex virus type 1 and 2 (HSV-1 and HSV-2) at different potencies except for Mulberrofuran G. Kuwanon X exhibited the greatest activity against HSV-1 15577 and clinical strains and HSV-2 strain 333 with IC 50 values of 2.2, 1.5 and 2.5 µg/mL, respectively. Further study revealed that Kuwanon X did not inactivate cell-free HSV-1 particles, but inhibited cellular adsorption and penetration of HSV-1 viral particles. Following viral penetration, Kuwanon X reduced the expression of HSV-1 IE and L genes, and decreased the synthesis of HSV-1 DNA. Furthermore, it was demonstrated that Kuwanon X inhibited the HSV-1-induced nuclear factor (NF)-κB activation through blocking the nuclear translocation and DNA binding of NF-κB. These results suggest that Kuwanon X exerts anti-HSV activity through multiple modes and could be a potential candidate for the therapy of HSV infection.Key words anti-herpes simplex virus (HSV) activity; Kuwanon X; penetration; gene expression; nuclear factor (NF)-κB; Mulberry Herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) are prevalent pathogens worldwide. HSV-1 is the main cause of orofacial herpes, cephalitis, corneal blindness, and several disorders of the peripheral nervous system; HSV-2 is usually associated with recurrent genital herpes, meningoencephalitis in neonates and meningitis in adults. Both HSV-1 and HSV-2 can cause latent infections in the neurons system, and then cause lesions at or near the point of entry into the body when they are reactivated.1,2) Recently, it was reported that HSV infections can increase the transmission of human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus type 1 (HTLV-1).3) During the productive infection, a successful HSV replication cycle is dependent on the completion of several steps, including α (immediate-early or IE), β (early or E), γ (late or L) genes and unpaired DNA replication based on sequential expression. The IE genes, such as UL54, encode transacting regulators of gene expression. The E genes, including UL52, are involved in viral DNA synthesis and nucleotide metabolism. The L genes, mainly encode structural proteins, e.g. ICP5 encoding the main capsid protein VP5.
4)The standard therapy for HSV infections are nucleoside analogues, such as acyclovir (ACV) and penciclovir. However, the emergence of HSV strains resistant to ACV remains an important clinical concern in immunocompromised individuals.5) Therefore, it is necessary to develop new antiherpetic agents with mechanisms of action different from that of nucleoside analogues.Mulberry (Morusalba L.) is widely cultivated in several Asian countries. Its leaves, fruits, twigs and root barks have long been used in Chinese medicine to reduce fever, maintain liver health, improve eyesight and lower blood pressure. Besides, Mulberry leaf is commonly...