Abstract
Rapid accumulation of viral proteins in host cells render viruses highly dependent on cellular chaperones including heat shock protein 90 (Hsp90). Three highly pathogenic human coronaviruses, including MERS-CoV, SARS-CoV and SARS-CoV-2, have emerged in the past 2 decades. However, there is no approved antiviral agent against these coronaviruses. We inspected the role of Hsp90 for coronavirus propagation. First, an Hsp90 inhibitor, 17-AAG, significantly suppressed MERS-CoV propagation in cell lines and physiological-relevant human intestinal organoids. Second, siRNA depletion of Hsp90β, but not Hsp90α, significantly restricted MERS-CoV replication and abolished virus spread. Third, Hsp90β interaction with MERS-CoV nucleoprotein (NP) was revealed in a co-immunoprecipitation assay. Hsp90β is required to maintain NP stability. Fourth, 17-AAG substantially inhibited the propagation of SARS-CoV and SARS-CoV-2. Collectively, Hsp90 is a host dependency factor for human coronavirus MERS-CoV, SARS-CoV and SARS-COV-2. Hsp90 inhibitors can be repurposed as a potent and broad-spectrum antiviral against human coronaviruses.
Keywords:
Coronavirus; Hsp90β; SARS-CoV-2; nucleoprotein; viral replication.
MeSH terms
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A549 Cells
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Animals
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Antiviral Agents / pharmacology*
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Benzoquinones / pharmacology*
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COVID-19 Drug Treatment
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Cell Line
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Chlorocebus aethiops
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HEK293 Cells
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HSP90 Heat-Shock Proteins / antagonists & inhibitors*
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HSP90 Heat-Shock Proteins / genetics*
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Host Microbial Interactions / drug effects*
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Humans
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Intestines / virology
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Lactams, Macrocyclic / pharmacology*
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Middle East Respiratory Syndrome Coronavirus / drug effects*
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Organ Culture Techniques
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RNA, Small Interfering
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SARS-CoV-2 / drug effects
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Severe acute respiratory syndrome-related coronavirus / drug effects
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Vero Cells
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Virus Replication / drug effects
Substances
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Antiviral Agents
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Benzoquinones
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HSP90 Heat-Shock Proteins
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Lactams, Macrocyclic
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RNA, Small Interfering
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tanespimycin
Grants and funding
This work was partly supported by funding from Health and Medical Research Fund [grant numbers 17161272, 19180392] of the Food and Health Bureau of the Hong Kong Special Administrative Region (HKSAR) to J.Z.; General Research Fund [grant number 17105420] of the Research Grants Council, HKSAR government to J.Z.; Theme-based Research Scheme [grant number T11-707/15-R] of the Research Grants Council, HKSAR Government to K.Y.Y.; the High Level Hospital-Summit Programme in Guangdong, The University of Hong Kong-Shenzhen Hospital to K.Y.Y.; and the donations of the Shaw Foundation Hong Kong, May Tam Mak Mei Yin, Richard Yu and Carol Yu, Michael Seak-Kan Tong, Respiratory Viral Research Foundation Limited, Hui Ming, Hui Hoy & Chow Sin Lan Charity Fund Limited, and Chan Yin Chuen Memorial Charitable Foundation to K.Y.Y.