Inhibition of herpes simplex virus infection by Caesappanin C targeting virus gB protein and host HSP90β

Background: The increasing drug resistance and limitations of conventional anti-herpes simplex virus (HSV) drugs highlight the urgent need for safer and more effective alternatives. Caesappanin C (CAP), derived from Caesalpinia sappan L., is recognized for its diverse biological properties, but its efficacy against HSV remains unexplored.

Purpose: To assess CAP's anti-HSV efficacy in vitro and in vivo, and to clarify its mechanisms.

Methods: CAP's anti-HSV activity in vitro was assessed using western blot, immunofluorescence assay and plaque assay. The anti-HSV mechanisms of CAP were investigated using membrane fusion, Co-IP and DARTS assays. Murine models of HSV-1 intranasal Infection model and HSV-2 genital herpes model were used to evaluate CAP's activity in vivo.

Results: CAP inhibited HSV replication across multiple cell types with minimal toxicity. CAP can effectively deactivate HSV particles and bind HSV surface glycoprotein B (gB) to inhibit membrane fusion. CAP also interacted with HSP90β to reduce the binding of HSP90β to STING thereby reducing HSV-induced inflammatory response. Furthermore, CAP markedly enhanced survival rates and alleviated inflammation in HSV-infected mice.

Conclusion: CAP effectively inhibits HSV by binding gB to prevent viral entry and interacting with HSP90β to diminish inflammatory responses. These results indicate that CAP derived from Caesalpinia sappan L. may have the potential to be an effective drug candidate against HSV.

Caesappanin C; Glycoprotein gB; HSP90; Herpes simplex virus; cGAS-STING.