Human coronavirus dependency on host heat shock protein 90 reveals an antiviral target

Emerg Microbes Infect. 2020 Dec;9(1):2663-2672. doi: 10.1080/22221751.2020.1850183.

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

  • A549 Cells
  • Animals
  • Antiviral Agents / pharmacology*
  • Benzoquinones / pharmacology*
  • COVID-19 Drug Treatment
  • Cell Line
  • Chlorocebus aethiops
  • HEK293 Cells
  • HSP90 Heat-Shock Proteins / antagonists & inhibitors*
  • HSP90 Heat-Shock Proteins / genetics*
  • Host Microbial Interactions / drug effects*
  • Humans
  • Intestines / virology
  • Lactams, Macrocyclic / pharmacology*
  • Middle East Respiratory Syndrome Coronavirus / drug effects*
  • Organ Culture Techniques
  • RNA, Small Interfering
  • SARS-CoV-2 / drug effects
  • Severe acute respiratory syndrome-related coronavirus / drug effects
  • Vero Cells
  • Virus Replication / drug effects

Substances

  • Antiviral Agents
  • Benzoquinones
  • HSP90 Heat-Shock Proteins
  • Lactams, Macrocyclic
  • RNA, Small Interfering
  • 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.