Emerg Microbes Infect. 2020 Dec;9(1):2663-2672. doi: 10.1080/22221751.2020.1850183.
Human coronavirus dependency on host heat shock protein 90 reveals an antiviral target
Cun Li 1 2, Hin Chu 1 2, Xiaojuan Liu 2, Man Chun Chiu 2, Xiaoyu Zhao 2, Dong Wang 2, Yuxuan Wei 2, Yuxin Hou 2, Huiping Shuai 2, Jianpiao Cai 2, Jasper Fuk-Woo Chan 1 2 3, Jie Zhou 1 2, Kwok Yung Yuen 1 2 3
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.
Antimicrob Agents Chemother. 2004 Mar; 48(3): 867–872.
Geldanamycin, a Ligand of Heat Shock Protein 90, Inhibits the Replication of Herpes Simplex Virus Type 1 In Vitro
Yu-Huan Li,1 Pei-Zhen Tao,1,* Yu-Zhen Liu,1 and Jian-Dong Jiang1,2
Geldanamycin (GA) is an antibiotic targeting the ADP/ATP binding site of heat shock protein 90 (Hsp90). In screening for anti-herpes simplex virus type 1 (HSV-1) candidates, we found GA active against HSV-1. HSV-1 replication in vitro was significantly inhibited by GA with an 50% inhibitory concentration of 0.093 μM and a concentration that inhibited cellular growth 50% in comparison with the results seen with untreated controls of 350 μM. The therapeutic index of GA was over 3,700 (comparable to the results seen with acyclovir). GA did not inhibit HSV-1 thymidine kinase. Cells infected with HSV-1 demonstrated cell cycle arrest at the G1/S transition; however, treatment with GA resulted in a cell cycle distribution pattern identical to that of untreated cells, indicating a restoration of cell growth in HSV-1-infected cells by GA treatment. Accordingly, HSV-1 DNA synthesis was suppressed in HSV-1+ cells treated with GA. The antiviral mechanism of GA appears to be associated with Hsp90 inactivation and cell cycle restoration, which indicates that GA exhibits broad-spectrum antiviral activity. Indeed, GA exhibited activities in vitro against other viruses, including severe acute respiratory syndrome coronavirus. Since GA inhibits HSV-1 through a cellular mechanism unique among HSV-1 agents, we consider it a new candidate agent for HSV-1.
Geldanamycin (GA) is a benzoquinone ansamycin and was first isolated as a new entity from the fermentation of Streptomyces hygroscopicus (3). GA binds with a high level of specificity within the ADP/ATP binding pocket of heat shock protein 90 (Hsp90) and inhibits the function of this chaperone (27, 36), resulting in inappropriately functioning and rapid degradation of Hsp90-associated client proteins (2, 28). The client proteins are mainly short-lived proteins, including several protein kinases (Raf-1, ErbB-2, and Bcr-Abl), p53, and pRb as well as cyclins and cyclin-dependent kinases (2, 25), which are degraded through the ubiquitin-proteasome pathway but protected by Hsp90 (4, 19). As a specific inhibitor of Hsp90 function, GA demonstrated antitumor activity in a multitude of animal models (23) and is now in clinical trial (phase I) in the United States (26). Interference with the function of Hsp90 seems to be the major mechanism of action of GA (29).
In a large-scale screening for novel candidates exhibiting activity against herpes simplex virus type 1 (HSV-1), we found (from the fermentation of S. hygroscopicus) a component active against HSV-1 replication. Chemical analysis of the purified compound showed a structure identical to that of GA. A study was then initiated to evaluate the potential of this compound in the treatment of HSV-1 infection. In the present study, the anti-HSV-1 effect of GA was examined in cell cultures. The possible molecular mechanism responsible for its activity against viral infection was also explored. Our investigation showed that the mode of action of GA was closely related to the inactivation of cellular Hsp90 and different from that seen with the viral enzyme inhibitors (such as viral DNA polymerase or thymidine kinase [TK] inhibitors). We consider these results informative with respect to antiviral research.
Biochimica et Biophysica Acta (BBA) – Molecular Cell Research. Volume 1823, Issue 3, March 2012, Pages 698-706
Broad action of Hsp90 as a host chaperone required for viral replication☆
Viruses are intracellular pathogens responsible for a vast number of human diseases. Due to their small genome size, viruses rely primarily on the biosynthetic apparatus of the host for their replication. Recent work has shown that the molecular chaperone Hsp90 is nearly universally required for viral protein homeostasis. As observed for many endogenous cellular proteins, numerous different viral proteins have been shown to require Hsp90 for their folding, assembly, and maturation. Importantly, the unique characteristics of viral replication cause viruses to be hypersensitive to Hsp90 inhibition, thus providing a novel therapeutic avenue for the development of broad-spectrum antiviral drugs. The major developments in this emerging field are hereby discussed. This article is part of a Special Issue entitled: Heat Shock Protein 90 (HSP90).
► Viruses are intracellular pathogens responsible for a vast number of human diseases. ► The molecular chaperone Hsp90 is nearly universally required for viral protein replication. ► The unique characteristics of viral replication cause viruses to be hypersensitive to pharmacological inhibitors of Hsp90. ► The ubiquitous requirement for Hsp90 provides a novel therapeutic avenue for development of broad-spectrum antiviral drugs.
Preprint from Research Square, 22 Mar 2020. DOI: 10.21203/rs.3.rs-18714/v1 PPR: PPR121665
Drug Repositioning Suggests a Role for the Heat Shock Protein 90 Inhibitor Geldanamycin in Treating COVID-19 Infection
Sultan I, Howard S, Tbakhi A
Drug repositioning offers an unmatched opportunity to offer novel therapeutics to treat SARS family of coronaviruses (SARS-FCoVs); an issue that became extremely urgent with the spreading of a novel virus with potential to threaten the lives of millions of people. Hereby, we analyzed a dataset of patients who presented with SARS during the 2003 outbreak. We established a gene signature that defines differential gene expression in patients who were sick with SARS vs. healthy controls and convalescent patients. We used a robust platform to conduct drug repositioning based on clustered gene expression and pathway enrichment to identify best matching drugs. We identified 55 agents of potential benefit. In most of these drugs we were able to establish a link to previous related research, use as antiviral, or at least a hypothetical role in treating SARS-FCoVs. Most notably, the heat shock protein 90 (hsp90) emerged as a major component that enables viruses to hijack infected cells through the process of autophagy. Almost half of the drugs identified could be linked to hsp90. As such, we propose using hsp90 inhibitors, mainly geldanamycin and its derivatives, to treat COVID-19.
nature Signal Transduction and Targeted Therapy volume 5, Article number: 125 (2020)
Stress proteins: the biological functions in virus infection, present and challenges for target-based antiviral drug development
Qianya Wan, Dan Song, Huangcan Li & Ming-liang He
Stress proteins (SPs) including heat-shock proteins (HSPs), RNA chaperones, and ER associated stress proteins are molecular chaperones essential for cellular homeostasis. The major functions of HSPs include chaperoning misfolded or unfolded polypeptides, protecting cells from toxic stress, and presenting immune and inflammatory cytokines. Regarded as a double-edged sword, HSPs also cooperate with numerous viruses and cancer cells to promote their survival. RNA chaperones are a group of heterogeneous nuclear ribonucleoproteins (hnRNPs), which are essential factors for manipulating both the functions and metabolisms of pre-mRNAs/hnRNAs transcribed by RNA polymerase II. hnRNPs involve in a large number of cellular processes, including chromatin remodelling, transcription regulation, RNP assembly and stabilization, RNA export, virus replication, histone-like nucleoid structuring, and even intracellular immunity. Dysregulation of stress proteins is associated with many human diseases including human cancer, cardiovascular diseases, neurodegenerative diseases (e.g., Parkinson’s diseases, Alzheimer disease), stroke and infectious diseases. In this review, we summarized the biologic function of stress proteins, and current progress on their mechanisms related to virus reproduction and diseases caused by virus infections. As SPs also attract a great interest as potential antiviral targets (e.g., COVID-19), we also discuss the present progress and challenges in this area of HSP-based drug development, as well as with compounds already under clinical evaluation.