Human Subtilase SKI-1/S1P Is a Master Regulator of the HCV Lifecycle and a Potential Host Cell Target for Developing Indirect-Acting Antiviral Agents

Most antiviral agents are designed to target virus-specific proteins and mechanisms rather than the host cell proteins that are critically dysregulated following virus-mediated reprogramming of the host cell transcriptional state. To overcome these limitations, we propose that elucidation and pharmacologic targeting of host cell Master Regulator proteins—whose aberrant activities govern the reprogramed state of infected-coronavirus cells—presents unique opportunities to develop novel mechanism-based therapeutic approaches to antiviral therapy, either as monotherapy or as a complement to established treatments. Specifically, we propose that a small module of host cell Master Regulator proteins (ViroCheckpoint) is hijacked by the virus to support its efficient replication and release. Conventional methodologies are not well suited to elucidate these potentially targetable proteins. By using the VIPER network-based algorithm, we successfully interrogated 12h, 24h, and 48h signatures from Calu-3 lung adenocarcinoma cells infected with SARS-CoV, to elucidate the time-dependent reprogramming of host cells and associated Master Regulator proteins. We used the NYS CLIA-certified Darwin OncoTreat algorithm, with an existing database of RNASeq profiles following cell perturbation with 133 FDA-approved and 195 late-stage experimental compounds, to identify drugs capable of virtually abrogating the virus-induced Master Regulator signature. This approach to drug prioritization and repurposing can be trivially extended to other viral pathogens, including SARS-CoV-2, as soon as the relevant infection signature becomes available.

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Identification of a host cell target for the thiazolide class of broad-spectrum anti-parasitic drugs

Experimental Parasitology ◽

10.1016/j.exppara.2011.02.007 ◽

2011 ◽

Vol 128 (2) ◽

pp. 145-150 ◽

Cited By ~ 16

Author(s):

Joachim Müller ◽

Andrew Hemphill

Keyword(s):

Host Cell ◽

Broad Spectrum ◽

Cell Target

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Host Cell Targets in HCV Therapy: Novel Strategy or Proven Practice?

Antiviral Chemistry and Chemotherapy ◽

10.1177/095632020501600201 ◽

2005 ◽

Vol 16 (2) ◽

pp. 69-90 ◽

Cited By ~ 8

Author(s):

Bert M Klebl ◽

Alexander Kurtenbach ◽

Kostas Salassidis ◽

Henrik Daub ◽

Thomas Herget

Keyword(s):

Hepatitis C Virus ◽

Hepatitis C ◽

Host Cell ◽

Kinase Inhibitors ◽

Antiviral Agents ◽

Cell Interaction ◽

Protein Kinase Inhibitors ◽

Research Progress ◽

Interferon Α ◽

Cellular Targets

The development of novel antiviral drugs against hepatitis C is a challenging and competitive area of research. Progress of this research has been hampered due to the quasispecies nature of the hepatitis C virus, the absence of cellular infection models and the lack of easily accessible and highly representative animal models. The current combination therapy consisting of interferon-α and ribavirin mainly acts by supporting host cell defence. These therapeutics are the prototypic representatives of indirect antiviral agents as they act on cellular targets. However, the therapy is not a cure, when considered from the long-term perspective, for almost half of the chronically infected patients. This draws attention to the urgent need for more efficient treatments. Novel anti-hepatitis C treatments under study are directed against a number of so-called direct antiviral targets such as polymerases and proteases, which are encoded by the virus. Although such direct antiviral approaches have proven to be successful in several viral indications, there is a risk of resistant viruses developing. In order to avoid resistance, the development of indirect antiviral compounds has to be intensified. These act on host cell targets either by boosting the immune response or by blocking the virus host cell interaction. A particularly interesting approach is the development of inhibitors that interfere with signal transduction, such as protein kinase inhibitors. The purpose of this review is to stress the importance of developing indirect antiviral agents that act on host cell targets. In doing so, a large source of potential targets and mechanisms can be exploited, thus increasing the likelihood of success. Ultimately, combination therapies consisting of drugs against direct and indirect viral targets will most probably provide the solution to fighting and eradicating hepatitis C virus in patients.

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Reduced interferon antagonism but similar drug sensitivity in Omicron variant compared to Delta variant SARS-CoV-2 isolates

10.1101/2022.01.03.474773 ◽

2022 ◽

Author(s):

Denisa Bojkova ◽

Marek Widera ◽

Sandra Ciesek ◽

Mark N Wass ◽

Martin Michaelis ◽

...

Keyword(s):

Host Cell ◽

Active Compound ◽

Drug Sensitivity ◽

Antiviral Agents ◽

Mechanistic Explanation ◽

Interferon Response ◽

Clinical Testing ◽

Drug Candidates ◽

Similar Drug ◽

Interferon Antagonism

The SARS-CoV-2 Omicron variant is currently causing a large number of infections in many countries. A number of antiviral agents are approved or in clinical testing for the treatment of COVID-19. Despite the high number of mutations in the Omicron variant, we here show that Omicron isolates display similar sensitivity to eight of the most important anti-SARS-CoV-2 drugs and drug candidates (including remdesivir, molnupiravir, and PF-07321332, the active compound in paxlovid), which is of timely relevance for the treatment of the increasing number of Omicron patients. Most importantly, we also found that the Omicron variant displays a reduced capability of antagonising the host cell interferon response. This provides a potential mechanistic explanation for the clinically observed reduced pathogenicity of Omicron variant viruses compared to Delta variant viruses.

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Ipomoeassin-F inhibits the in vitro biogenesis of the SARS-CoV-2 spike protein and its host cell membrane receptor

Journal of Cell Science ◽

10.1242/jcs.257758 ◽

2021 ◽

Vol 134 (4) ◽

pp. jcs257758 ◽

Cited By ~ 1

Author(s):

Sarah O'Keefe ◽

Peristera Roboti ◽

Kwabena B. Duah ◽

Guanghui Zong ◽

Hayden Schneider ◽

...

Keyword(s):

Host Cell ◽

Protein Translocation ◽

Antiviral Agents ◽

Membrane Receptor ◽

Host Cell Membrane ◽

Cell Plasma ◽

Molecule Inhibitor ◽

Plasma Membrane Receptor ◽

Human Viruses

ABSTRACTIn order to produce proteins essential for their propagation, many pathogenic human viruses, including SARS-CoV-2, the causative agent of COVID-19 respiratory disease, commandeer host biosynthetic machineries and mechanisms. Three major structural proteins, the spike, envelope and membrane proteins, are amongst several SARS-CoV-2 components synthesised at the endoplasmic reticulum (ER) of infected human cells prior to the assembly of new viral particles. Hence, the inhibition of membrane protein synthesis at the ER is an attractive strategy for reducing the pathogenicity of SARS-CoV-2 and other obligate viral pathogens. Using an in vitro system, we demonstrate that the small molecule inhibitor ipomoeassin F (Ipom-F) potently blocks the Sec61-mediated ER membrane translocation and/or insertion of three therapeutic protein targets for SARS-CoV-2 infection; the viral spike and ORF8 proteins together with angiotensin-converting enzyme 2, the host cell plasma membrane receptor. Our findings highlight the potential for using ER protein translocation inhibitors such as Ipom-F as host-targeting, broad-spectrum antiviral agents.This article has an associated First Person interview with the first author of the paper.

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Ipomoeassin-F inhibits the in vitro biogenesis of the SARS-CoV-2 spike protein and its host cell membrane receptor

10.1101/2020.11.24.390039 ◽

2020 ◽

Author(s):

Sarah O’Keefe ◽

Peristera Roboti ◽

Kwabena B. Duah ◽

Guanghui Zong ◽

Hayden Schneider ◽

...

Keyword(s):

Host Cell ◽

Protein Translocation ◽

Antiviral Agents ◽

Membrane Receptor ◽

Host Cell Membrane ◽

Cell Plasma ◽

Molecule Inhibitor ◽

Plasma Membrane Receptor ◽

Human Viruses

AbstractIn order to produce proteins essential for their propagation, many pathogenic human viruses, including SARS-CoV-2 the causative agent of COVID-19 respiratory disease, commandeer host biosynthetic machineries and mechanisms. Three major structural proteins, the spike, envelope and membrane proteins, are amongst several SARS-CoV-2 components synthesised at the endoplasmic reticulum (ER) of infected human cells prior to the assembly of new viral particles. Hence, the inhibition of membrane protein synthesis at the ER is an attractive strategy for reducing the pathogenicity of SARS-CoV-2 and other obligate viral pathogens. Using an in vitro system, we demonstrate that the small molecule inhibitor ipomoeassin F (Ipom-F) potently blocks the Sec61-mediated ER membrane translocation/insertion of three therapeutic protein targets for SARS-CoV-2 infection; the viral spike and ORF8 proteins together with angiotensin-converting enzyme 2, the host cell plasma membrane receptor. Our findings highlight the potential for using ER protein translocation inhibitors such as Ipom-F as host-targeting, broad-spectrum, antiviral agents.

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