Clinical HDAC Inhibitors Are Effective Drugs to Prevent the Entry of SARS-CoV2
Ke Liu,#† Rongfeng Zou,#† Wenqiang Cui,#†∥ Meiqing Li,#†∥ Xueying Wang,† Junlin Dong,† Hongchun Li,† Hongpei Li,‡ Peihui Wang,§ Ximing Shao,† Wu Su,† H. C. Stephen Chan,corresponding author*† Hongchang Li,corresponding author*† and Shuguang Yuancorresponding author*†
ACS Pharmacol Transl Sci. 2020 Nov 10 : acsptsci.0c00163.
The outbreak of COVID-19 by the end of 2019 has posed serious health threats to humanity and jeopardized the global economy. However, no effective drugs are available to treat COVID-19 currently and there is a great demand to fight against it. Here, we combined computational screening and an efficient cellular pseudotyped virus system, confirming that clinical HDAC inhibitors can efficiently prevent SARS-CoV-2 and potentially be used to fight against COVID-19.
MOLECULAR DOCKING STUDY REVEALS THE POTENTIAL REPURPOSING OF HISTONE DEACETYLASE INHIBITORS AGAINST COVID-19
Mamdouh F. A. Mohamed * 1, Gamal El-Din A. Abuo-Rahma 2, Alaa M. Hayallah 3, 4, Marwa A. Aziz 2, Ayman Nafady 5 and Ebtihal Samir 6
INTERNATIONAL JOURNAL OF PHARMACEUTICAL SCIENCES AND RESEARCH
The outburst of new coronavirus (COVID-19) infections, firstly appeared in Wuhan in 2019, has massively expanded to the whole world. At the end of March 2020, the rapid spread of the infection happened in about 206 countries around the globe. At the moment, the statistics of WHO on coronavirus pandemic revealed total infected cases of 21,770,000 and more than 77,000 deaths all over the world, with no proven antiviral agent available yet to control COVID-19 infection. The world is currently in desperate need of finding potent therapeutic agents. Histone deacetylases (HDACs) represent one of the most promising viral targets. Importantly, HDACs are critical factors involved in the control of viral replication. The molecular mechanisms associated with underlying the role of HDACs in viral latency, viral reactivation, and carcinogenesis are progressively disclosed. Till now, six HDACIs anticancer drugs have been approved by the FDA. Herein, in the in-silico structure-based drug design approach was utilized to identify novel structural characteristics for the potential repurposed activity of HDACIs as antivirals for COVID-19. In this respect, 12 HDACIs were carefully screened to probe their possible anti-viral activity against SARS-CoV main proteaseMpro (PDB: 6LU7). Most of the screened HDACIs are strongly bind into the active binding site of crystallographic structure of Mpro (PDB: 6LU7) with comparable docking energy and hydrogen bond formation. These findings demonstrate that HDACIs, especially Romidepsin and its active form (RedFK), hold promise as COVID-19 protease inhibitors. Moreover, calculations of physicochemical parameters and drug-likeness properties of the screened compounds implied an acceptable ADMET for all tested compounds.
Histone deacetylase inhibitors suppress RSV infection and alleviate virus-induced airway inflammation
Qiuqin Feng 1, Zhonglan Su 2, Shiyu Song 1, Hui Χu 1, Bin Zhang 1, Long Yi 1, Man Tian 3, Hongwei Wang 1
Int J Mol Med. 2016 Sep;38(3):812-22. doi: 10.3892/ijmm.2016.2691. Epub 2016 Jul 26.
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants and young children. However, the majority of RSV-infected patients only show mild symptoms. Different severities of infection and responses among the RSV-infected population indicate that epigenetic regulation as well as personal genetic background may affect RSV infectivity. Histone deacetylase (HDAC) is an important epigenetic regulator in lung diseases. The present study aimed to explore the possible connection between HDAC expression and RSV-induced lung inflammation. To address this question, RSV-infected airway epithelial cells (BEAS‑2B) were prepared and a mouse model of RSV infection was established, and then treated with various concentrations of HDAC inhibitors (HDACis), namely trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA). Viral replication and markers of virus-induced airway inflammation or oxidative stress were assessed. The activation of the nuclear factor-κB (NF-κB), cyclo-oxygenase-2 (COX-2), mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) signaling pathways was evaluated by western blot analysis. Our results showed that RSV infection in airway epithelial cells (AECs) significantly decreased histone acetylation levels by altering HDAC2 expression. The treatment of RSV-infected AECs with HDACis significantly restricted RSV replication by upregulating the interferon-α (IFN-α) related signaling pathways. The treatment of RSV-infected AECs with HDACis also significantly inhibited RSV-induced pro-inflammatory cytokine release [interleukin (IL)-6 and IL-8] and oxidative stress-related molecule production [malondialdehyde (MDA), and nitrogen monoxide (NO)]. The activation of NF-κB, COX-2, MAPK and Stat3, which orchestrate pro‑inflammatory gene expression and oxidative stress injury, was also significantly inhibited. Our in vivo study using a mouse model of RSV infection validated these results. Treatment with HDACis alleviated airway inflammation and reduced in vivo RSV replication. Our data demonstrated that RSV reduced histone acetylation by enhancing HDAC2 expression. Treatment with HDACis (TSA/SAHA) significantly inhibited RSV replication and decreased RSV-induced airway inflammation and oxidative stress. Therefore, the inhibition of HDACs represents a novel therapeutic approach in modulating RSV-induced lung disease.
Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication
Bratati Sahaa,b,c and Robin J. Parkscorresponding authora,b,c,d
J Virol. 2019 Jun 15; 93(12): e00088-19. Published online 2019 May 29.
Human adenovirus (HAdV) causes minor illnesses in most patients but can lead to severe disease and death in pediatric, geriatric, and immunocompromised individuals. No approved antiviral therapy currently exists for the treatment of these severe HAdV-induced diseases. In this study, we show that the pan-histone deacetylase (HDAC) inhibitor SAHA reduces HAdV-5 gene expression and DNA replication in tissue culture, ultimately decreasing virus yield from infected cells. Importantly, SAHA also reduced gene expression from more virulent and clinically relevant serotypes, including HAdV-4 and HAdV-7. In addition to SAHA, several other HDAC inhibitors (e.g., trichostatin A, apicidin, and panobinostat) also affected HAdV gene expression. We determined that loss of class I HDAC activity, mainly HDAC2, impairs efficient expression of viral genes, and that E1A physically interacts with HDAC2. Our results suggest that HDAC activity is necessary for HAdV replication, which may represent a novel pharmacological target in HAdV-induced disease.
IMPORTANCE Although human adenovirus (HAdV) can cause severe diseases that can be fatal in some populations, there are no effective treatments to combat HAdV infection. In this study, we determined that the pan-histone deacetylase (HDAC) inhibitor SAHA has inhibitory activity against several clinically relevant serotypes of HAdV. This U.S. Food and Drug Administration-approved compound affects various stages of the virus lifecycle and reduces virus yield even at low concentrations. We further report that class I HDAC activity, particularly HDAC2, is required for efficient expression of viral genes during lytic infection. Investigation of the mechanism underlying SAHA-mediated suppression of HAdV gene expression and replication will enhance current knowledge of virus-cell interaction and may aid in the development of more effective antivirals with lower toxicity for the treatment of HAdV infections.
Cellular defence or viral assist: the dilemma of HDAC6
Kai Zheng 1 2, Yingchun Jiang 1, Zhendan He 1, Kaio Kitazato 3, Yifei Wang 2
J Gen Virol. 2017 Mar;98(3):322-337. doi: 10.1099/jgv.0.000679. Epub 2017 Apr 1.
Histone deacetylase 6 (HDAC6) is a unique cytoplasmic deacetylase that regulates various important biological processes by preventing protein aggregation and deacetylating different non-histone substrates including tubulin, heat shock protein 90, cortactin, retinoic acid inducible gene I and β-catenin. Growing evidence has indicated a dual role for HDAC6 in viral infection and pathogenesis: HDAC6 may represent a host defence mechanism against viral infection by modulating microtubule acetylation, triggering antiviral immune response and stimulating protective autophagy, or it may be hijacked by the virus to enhance proinflammatory response. In this review, we will highlight current data illustrating the complexity and importance of HDAC6 in viral pathogenesis. We will summarize the structure and functional specificity of HDAC6, and its deacetylase- and ubiquitin-dependent activity in key cellular events in response to virus infection. We will also discuss how HDAC6 exerts its direct or indirect histone modification ability in viral lytic-latency switch.
A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing
David E. Gordon, et al.
Version 1. bioRxiv. Preprint. 2020 Mar 22. doi: 10.1101/2020.03.22.002386
An outbreak of the novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 290,000 people since the end of 2019, killed over 12,000, and caused worldwide social and economic disruption1,2. There are currently no antiviral drugs with proven efficacy nor are there vaccines for its prevention. Unfortunately, the scientific community has little knowledge of the molecular details of SARS-CoV-2 infection. To illuminate this, we cloned, tagged and expressed 26 of the 29 viral proteins in human cells and identified the human proteins physically associated with each using affinity- purification mass spectrometry (AP-MS), which identified 332 high confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 existing FDA-approved drugs, drugs in clinical trials and/or preclinical compounds, that we are currently evaluating for efficacy in live SARS-CoV-2 infection assays. The identification of host dependency factors mediating virus infection may provide key insights into effective molecular targets for developing broadly acting antiviral therapeutics against SARS-CoV-2 and other deadly coronavirus strains.