Bortezomib inhibits ZIKV/DENV by interfering with viral polyprotein cleavage via the ERAD pathway

Yali Ci; Bin Yao; Kun Yue; Yang Yang; Caimin Xu; De-Feng Li; Cheng-Feng Qin; Lei Shi

doi:10.1016/j.chembiol.2022.10.003

Bortezomib inhibits ZIKV/DENV by interfering with viral polyprotein cleavage via the ERAD pathway

Cell Chem Biol. 2023 May 18;30(5):527-539.e5. doi: 10.1016/j.chembiol.2022.10.003. Epub 2022 Nov 8.

Authors

Yali Ci¹, Bin Yao¹, Kun Yue¹, Yang Yang¹, Caimin Xu¹, De-Feng Li², Cheng-Feng Qin³, Lei Shi⁴

Affiliations

¹ State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China; Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China.
² State Key Laboratory of Microbial Resources, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China.
³ State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China.
⁴ State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China; Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical College, Beijing 100005, China. Electronic address: shilei@ibms.pumc.edu.cn.

PMID: 36351431
DOI: 10.1016/j.chembiol.2022.10.003

Abstract

Flaviviruses have posed a serious threat to human health in the past decades, and effective therapeutic drugs are lacking; thus, treatment of flavivirus infection is a great challenge. The flavivirus protease NS2B3 is an attractive target for antiviral drug screening. Here, we developed an intracellular Zika virus (ZIKV) NS2AB3 self-cleavage assay to identify inhibitors that interfere with viral polyprotein cleavage and block ZIKV/dengue virus (DENV) replication. Bortezomib was identified as the most potent inhibitor, with a half-maximal effective concentration (EC50) in the nanomolar range. We found that instead of directly inhibiting NS2B3 protease activity, bortezomib dramatically induced the ubiquitination and aggregation of NS3, leading to the attenuation of its protease activity in cells. Two E3 ligases, HRD1 and RNF126, were found to be responsible for NS3 ubiquitination. Our study identifies bortezomib as a potential drug for the treatment of ZIKV/DENV infection and reveals the central role of the ERAD pathway in the inhibition of flaviviruses by bortezomib.

Keywords: E3 ligase; ERAD; NS2B3 protease; bortezomib; flavivirus; inhibitor; ubiquitination.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bortezomib / metabolism
Dengue Virus*
Endoplasmic Reticulum-Associated Degradation
Flavivirus*
Humans
Ubiquitin-Protein Ligases / metabolism
Zika Virus Infection* / drug therapy
Zika Virus*

Substances

Bortezomib
RNF126 protein, human
Ubiquitin-Protein Ligases