Suppression of herpes simplex virus type 1 replication by Pin1 inhibitors: insights from H-77 and novel compounds

Herpes simplex virus type 1 (HSV-1) infection is widespread globally, necessitating the development of new therapeutic approaches. Previous studies have demonstrated that peptidyl-prolyl cis/trans isomerase Pin1 is essential for the replication of cytomegalovirus, a member of the herpesvirus family. Our research demonstrated that Pin1 knockdown significantly suppressed HSV-1 replication. Furthermore, we found that our Pin1 inhibitor H-77, along with four novel Pin1 inhibitors, also inhibited HSV-1 replication. The 50 % effective concentration (EC₅₀) of H-77 against HSV-1 replication in VeroE6 cells was 0.75 μM. In HSV-1-infected cells treated with H-77, expression levels of the immediate early viral protein ICP0 and late viral proteins VP5 and glycoprotein C (gC) were significantly reduced, indicating suppression of viral protein expression. Immunofluorescence staining revealed that in H-77-treated cells, viral proteins including VP5 were confined within the nucleus by an intact nuclear lamina. Transmission electron microscopy analysis demonstrated that H-77-treated cells exhibited markedly fewer extracellular viral particles, with nucleocapsid nuclear egress being inhibited. These results demonstrate that H-77 suppresses HSV-1 replication through dual mechanisms: inhibition of viral protein synthesis and blockade of nucleocapsid nuclear egress. These findings indicate that Pin1 represents a promising therapeutic target for HSV-1 inhibition, warranting further development of Pin1 inhibitors as anti-HSV-1 agents.