Novel Hsp90α inhibitor inhibits HSV-1 infection by suppressing the Akt/β-catenin pathway.

The prevalence of herpes simplex virus type 1 (HSV-1) infection and the emergence of drug-resistant HSV-1 strains posts a significant global health challenge, necessitating the urgent development of effective anti-HSV-1 drugs. As one of the most prevalent molecular chaperones, heat shock protein 90 α (Hsp90α) has been extensively demonstrated to regulate a range of viral infections, thus representing a promising antiviral target. In this study, we identified JD-13 as a novel Hsp90α inhibitor and explored its capability in inhibiting HSV-1 infection. The inhibitory effect of JD-13 on Hsp90α activity was confirmed by molecular docking, molecular dynamic stimulations, fluorescence quench titration and cellular thermal shift assay. Furthermore, we found that JD-13 significantly inhibits the infection of both normal and acyclovir-resistant HSV-1 strains. In addition, JD-13 alleviated skin damage in guinea pigs caused by cutaneous HSV-1 infection. Further studies revealed that JD-13 impaired HSV-1 early infection and suppressed the Akt/β-catenin signaling pathway by promoting Akt degradation. Consequently, the inhibition of the Akt/β-catenin signaling pathway restricted HSV-1 infection. In conclusion, these results suggest JD-13 as a novel HSP90α inhibitor with the potential to be developed as an antiviral agent for the treatment of HSV-1-related diseases.