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. 2019 Aug:166:82-92.
doi: 10.1016/j.bcp.2019.05.003. Epub 2019 May 6.

AT-533, a Hsp90 inhibitor, attenuates HSV-1-induced inflammation

Feng Li  1 , Xiaowei Song  1 , Guifeng Su  1 , Yiliang Wang  1 , Zhaoyang Wang  1 , Shurong Qing  1 , Jiaoyan Jia  1 , Yuan Wang  1 , Lianzhou Huang  1 , Kai Zheng  2 , Yifei Wang  3
Affiliations

AT-533, a Hsp90 inhibitor, attenuates HSV-1-induced inflammation

Feng Li et al. Biochem Pharmacol. 2019 Aug.

Abstract

Inflammatory events are tightly associated with the death caused by Herpes simplex virus 1 (HSV-1) infection of the brain. Heat shock protein 90 (Hsp90) is a molecular chaperone that is stimulated in response to many stressful conditions (e.g., inflammation and hypoxia) and Hsp90 inhibitors are suggested to be potent inhibitors of the inflammatory response. The aim of this study was to investigate the effect of Hsp90 inhibitor AT-533 on HSV-1-induced inflammation. AT-533 at a non-antiviral concentration was found to show a prominent inhibitory effect on the production of cytokines induced by HSV-1 infection, such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6) and interleukin 1β (IL-1β). Mechanically, HSV-1 early infection induced inflammation through NF-κB signaling and NLRP3 inflammasome activation, as illustrated by the nuclear translocation of NF-κB and the enhanced cleavage of caspase-1. Besides, HSV-1 enhanced the interaction between NLRP3 and Hsp90. Moreover, AT-533 reduced the nuclear translocation of NF-κB and inflammasome activation via inhibiting the chaperone function of Hsp90. Furthermore, AT-533 inhibited the cleavage of pro-IL-1β to mature IL-1β in a NLRP3-independent manner. In summary, AT-533 may be a promising therapeutic strategy in HSV-1-infected inflammation management.

Keywords: HSV-1; Hsp90; Inflammation; NF-κB; NLRP3 inflammasome.

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