BRD4 inhibition exerts anti-viral activity through DNA damage-dependent innate immune responses
Jiang Wang, Conceptualization, Data curation, Formal analysis, Methodology, Writing – original draft, Writing – review & editing,#1 Guo-Li Li, Investigation, Methodology,#1 Sheng-Li Ming, Investigation, Methodology,#1 Chun-Feng Wang, Investigation,#1 Li-Juan Shi, Investigation,1 Bing-Qian Su, Investigation,1 Hong-Tao Wu, Investigation,1 Lei Zeng, Investigation,1 Ying-Qian Han, Investigation,1 Zhong-Hu Liu, Conceptualization,1 Da-Wei Jiang, Funding acquisition, Investigation,1 Yong-Kun Du, Funding acquisition, Investigation,1 Xiang-Dong Li, Methodology,2 Gai-Ping Zhang, Conceptualization, Funding acquisition,1 Guo-Yu Yang, Conceptualization, Funding acquisition, Supervision,1,* and Bei-Bei Chu, Conceptualization, Formal analysis, Funding acquisition, Supervision, Writing – original draft, Writing – review & editing1,*
PLoS Pathog. 2020 Mar; 16(3): e1008429. Published online 2020 Mar 24.
Chromatin dynamics regulated by epigenetic modification is crucial in genome stability and gene expression. Various epigenetic mechanisms have been identified in the pathogenesis of human diseases. Here, we examined the effects of ten epigenetic agents on pseudorabies virus (PRV) infection by using GFP-reporter assays. Inhibitors of bromodomain protein 4 (BRD4), which receives much more attention in cancer than viral infection, was found to exhibit substantial anti-viral activity against PRV as well as a range of DNA and RNA viruses. We further demonstrated that BRD4 inhibition boosted a robust innate immune response. BRD4 inhibition also de-compacted chromatin structure and induced the DNA damage response, thereby triggering the activation of cGAS-mediated innate immunity and increasing host resistance to viral infection both in vitro and in vivo. Mechanistically, the inhibitory effect of BRD4 inhibition on viral infection was mainly attributed to the attenuation of viral attachment. Our findings reveal a unique mechanism through which BRD4 inhibition restrains viral infection and points to its potent therapeutic value for viral infectious diseases.
Bromodomain Inhibitors as Therapeutics for Herpesvirus-Related Disease: All BETs Are Off?
Ian J. Groves*†, John H. Sinclair† and Mark R. Wills†
Front. Cell. Infect. Microbiol., 02 July 2020 | https://doi.org/10.3389/fcimb.2020.00329
Although the ubiquitous human herpesviruses (HHVs) are rarely associated with serious disease of the healthy host, primary infection and reactivation in immunocompromised individuals can lead to significant morbidity and, in some cases, mortality. Effective drugs are available for clinical treatment, however resistance is on the rise such that new anti-viral targets, as well as novel clinical treatment strategies, are required. A promising area of development and pre-clinical research is that of inhibitors of epigenetic modifying proteins that control both cellular functions and the viral life cycle. Here, we briefly outline the interaction of the host bromo- and extra-terminal domain (BET) proteins during different stages of the HHVs’ life cycles while giving a full overview of the published work using BET bromodomain inhibitors (BRDis) during HHV infections. Furthermore, we provide evidence that small molecule inhibitors targeting the host BET proteins, and BRD4 in particular, have the potential for therapeutic intervention of HHV-associated disease.
A proteomic model of SARS-COV2 infection by comparing the interactomes of BRD4 with BET-inhibition and SARS-COV2 viral proteins – implications for re-purposing approved drugs or ubiquitin-mediated degradation of select candidates
The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected 2,029,930 people worldwide and caused 136,320 deaths. Consequently, the hunt for drugs showing efficacy against this deadly disease, or vaccines for prevention, are being intensely investigated. Unfortunately, there is a scarcity of research data on the molecular mechanisms of SARS-CoV-2 infection for quickly finding effective therapies, or repurposing existing drugs approved by the US FDA. This report models existing knowledge of SARS-COV2 viral proteins and the cellular proteins they interact with by comparisons with BRD4 interacting proteins identified from B cells, with or without BET inhibition. The E protein of SARS-COV2 interacts with BRD4, and the Spike (S) protein with CANX. Extensive similarities were observed with published cellular interactants of 13 SARS-COV2 proteins resulting in 47 BRD4-interacting protein candidates, with or without BET inhibition. 61 cellular protein targets and 132 FDA approved drugs which use these proteins as targets are proposed, which can be investigated for efficacy against SARS-COV2 infections. The implications to SARS-COV2 disease diagnosis, therapy and vaccine creation are discussed.
A SARS-CoV-2 protein interaction map reveals targets for drug repurposing
David E. Gordon, Gwendolyn M. Jang, […]Nevan J. Krogan
Nature volume 583, pages459–468(2020)Cite this article
A newly described coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is the causative agent of coronavirus disease 2019 (COVID-19), has infected over 2.3 million people, led to the death of more than 160,000 individuals and caused worldwide social and economic disruption1,2. There are no antiviral drugs with proven clinical efficacy for the treatment of COVID-19, nor are there any vaccines that prevent infection with SARS-CoV-2, and efforts to develop drugs and vaccines are hampered by the limited knowledge of the molecular details of how SARS-CoV-2 infects cells. Here we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins that physically associated with each of the SARS-CoV-2 proteins using affinity-purification mass spectrometry, identifying 332 high-confidence protein–protein interactions between SARS-CoV-2 and human proteins. Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (of which, 29 drugs are approved by the US Food and Drug Administration, 12 are in clinical trials and 28 are preclinical compounds). We screened a subset of these in multiple viral assays and found two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the sigma-1 and sigma-2 receptors. Further studies of these host-factor-targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
Identification of key genes in SARS-CoV-2 patients on bioinformatics analysis
Gu H, Yuan G
Preprint from bioRxiv, 11 Aug 2020
Abstract The COVID-19 pandemic has infected millions of people and overwhelmed many health systems globally. Our study is to identify differentially expressed genes (DEGs) and associated biological processes of COVID-19 using a bioinformatics approach to elucidate their potential pathogenesis. The gene expression profiles of the GSE152075 datasets were originally produced by using the high-throughput Illumina NextSeq 500. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were performed to identify functional categories and biochemical pathways. GO and KEGG results suggested that several biological pathways such as “Fatty acid metabolism” and “Cilium morphogenesis” are mostly involved in the development of COVID-19. Moreover, several genes are critical for virus invasion and adhesion including FLOC, DYNLL1, FBXL3, and FBXW11 and show significant differences in COVID-19 patients. Thus, our study provides further insights into the underlying pathogenesis of COVID-19.
Identification of potential biomarkers and inhibitors for SARS-CoV-2 infection
Hanming Gu, View ORCID ProfileGongsheng Yuan
medRxiv. doi: https://doi.org/10.1101/2020.09.15.20195487. This article is a preprint.
The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has overwhelmed many health systems globally. Here, we aim to identify biological markers and associated biological processes of COVID-19 using a bioinformatics approach to elucidate their potential pathogenesis. The gene expression profile of the GSE152418 dataset was originally produced by using the high-throughput Illumina NovaSeq 6000. Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) and Gene Ontology (GO) enrichment analyses were applied to identify functional categories and biochemical pathways. KEGG and GO results suggested that biological pathways such as Cancer pathways and Insulin pathways were mostly affected in the development of COVID-19. Moreover, we identified several genes including EP300, CREBBP, and POLR2A were involved in the virus activities in COVID-19 patients. We further predicted that some inhibitors may have the potential to block the SARS-CoV-2 infection based on the L1000FWD analysis. Therefore, our study provides further insights into the underlying pathogenesis of COVID-19.