Hsp90 Inhibitors Prevent HSV-1 Replication by Directly Targeting UL42-Hsp90 Complex.

Shurong Qin,Yifei Wang,Ji Xiao,Xiao Hu,Jiaoyan Jia,Zhe Ren,Shimin Lin,Zhaoyang Wang,Kaisheng Liu,Xiaowei Song

doi:10.3389/fmicb.2021.797279

Shurong Qin, Yifei Wang + Show 8 more

Open Access

https://doi.org/10.3389/fmicb.2021.797279

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Abstract

Herpes simplex virus type I (HSV-1) is a member of the Alphaherpesvirinae family, which could initiate labial herpes caused by the reactivation of HSV-1 primary infection, and secondary infection even causes herpes encephalitis. The study presented here demonstrates that Hsp90 inhibitors (AT-533 and 17-AAG) directly targeted the HSV-1 UL42-Hsp90 complex, and Hsp90 interacted with HSV-1 UL42 in silicon and experiment. Interestingly, Hsp90 inhibitors also reduced virus titers of ACV-resistant clinical HSV-1 strains (153 and blue strain), revealing that HSV-1 UL42 would be a new target against ACV-resistant HSV-1 strains. Altogether, this present study indicates that Hsp90 inhibitors prevent HSV-1 proliferation by regulating the interaction between Hsp90 and HSV-1 UL42, suggesting a promising target for anti-HSV-1 therapies in the replication.

Highlights

Herpes simplex virus-1 (HSV-1), a common human pathogenic virus, belongs to the α Herpesviridae family (Yoshikawa, 2000)
heat shock protein 90 (Hsp90) interacted with the Epstein-Barr virus (EBV) DNA polymerase processivity factor BMRF1 in the cytoplasm to assist complex formation with polymerase catalytic subunit BALF5, indicating the interaction between Hsp90 and its client protein BMRF1 is vital for EBV genome synthesis and disease development (Kawashima et al, 2013)
Several studies have demonstrated that Hsp90 participates in many HSV-1 infectious stages, including early and late stages, which indicates that Hsp90 is a promising candidate for novel drug targets (Wang et al, 2017)

Summary

Introduction

Herpes simplex virus-1 (HSV-1), a common human pathogenic virus, belongs to the α Herpesviridae family (Yoshikawa, 2000). HSV-1 contains at least 7 conserved proteins to regulate DNA replication, such as origin-binding protein UL9, single-stranded DNA binding protein ICP8, DNA polymerase complex UL30/42 and helicase-primase complex UL5/8/52 (James et al, 2015). Among the most important HSV-1 proteins, HSV-1 DNA polymerase and the early enzyme thymidine kinase (TK) play a key role in the virus replication process, so drugs targeting these proteins may disrupt the viral replication cycle (Souza et al, 2008). Nucleic acid analogs have been used as anti-HSV-1 drugs in the clinical frontline, which targets the stage of viral DNA replication, especially acting on TK. It is crucial to develop novel antiviral drugs targeting different life stages

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