scholarly journals Antiviral activity of Glucosylceramide synthase inhibitors against SARS-CoV-2 and other RNA virus infections

2020 ◽  
Author(s):  
Einat. B. Vitner ◽  
Roy Avraham ◽  
Hagit Achdout ◽  
Hadas Tamir ◽  
Avi Agami ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Cell Membranes ◽  
Rna Viruses ◽  
Rna Virus ◽  
Antiviral Drugs ◽  
Membrane Dynamics ◽  
Biologically Active ◽  
Phase Iii ◽  
Glucosylceramide Synthase

AbstractThe need for antiviral drugs is real and relevant. Broad spectrum antiviral drugs have a particular advantage when dealing with rapid disease outbreaks, such as the current COVID-19 pandemic. Since viruses are completely dependent on internal cell mechanisms, they must cross cell membranes during their lifecycle, creating a dependence on processes involving membrane dynamics. Thus, in this study we examined whether the synthesis of glycosphingolipids, biologically active components of cell membranes, can serve as an antiviral therapeutic target. We examined the antiviral effect of two specific inhibitors of GlucosylCeramide synthase (GCS); (i) Genz-123346, an analogue of the FDA-approved drug Cerdelga®, (ii) GENZ-667161, an analogue of venglustat which is currently under phase III clinical trials. We found that both GCS inhibitors inhibit the replication of four different enveloped RNA viruses of different genus, organ-target and transmission route: (i) Neuroinvasive Sindbis virus (SVNI), (ii) West Nile virus (WNV), (iii) Influenza A virus, and (iv) SARS-CoV-2. Moreover, GCS inhibitors significantly increase the survival rate of SVNI-infected mice. Our data suggest that GCS inhibitors can potentially serve as a broad-spectrum antiviral therapy and should be further examined in preclinical and clinical trial. Analogues of the specific compounds tested have already been studied clinically, implying they can be fast-tracked for public use. With the current COVID-19 pandemic, this may be particularly relevant to SARS-CoV-2 infection.One Sentence SummaryAn analogue of Cerdelga®, an FDA-approved drug, is effective against a broad range of RNA-viruses including the newly emerging SARS-CoV-2.

scholarly journals Targeting viral genome synthesis as broad-spectrum approach against RNA virus infections

2020 ◽  
Vol 28 ◽  
pp. 204020662097678
Author(s):  
Johanna Huchting
Keyword(s):  
Broad Spectrum ◽  
Viral Genome ◽  
De Novo ◽  
Rna Viruses ◽  
Rna Virus ◽  
Antiviral Drug ◽  
Building Blocks ◽  
Structural Features ◽  
Pathogen Transmission ◽  
Nucleotide Synthesis

Zoonotic spillover, i.e. pathogen transmission from animal to human, has repeatedly introduced RNA viruses into the human population. In some cases, where these viruses were then efficiently transmitted between humans, they caused large disease outbreaks such as the 1918 flu pandemic or, more recently, outbreaks of Ebola and Coronavirus disease. These examples demonstrate that RNA viruses pose an immense burden on individual and public health with outbreaks threatening the economy and social cohesion within and across borders. And while emerging RNA viruses are introduced more frequently as human activities increasingly disrupt wild-life eco-systems, therapeutic or preventative medicines satisfying the “one drug-multiple bugs”-aim are unavailable. As one central aspect of preparedness efforts, this review digs into the development of broadly acting antivirals via targeting viral genome synthesis with host- or virus-directed drugs centering around nucleotides, the genomes’ universal building blocks. Following the first strategy, selected examples of host de novo nucleotide synthesis inhibitors are presented that ultimately interfere with viral nucleic acid synthesis, with ribavirin being the most prominent and widely used example. For directly targeting the viral polymerase, nucleoside and nucleotide analogues (NNAs) have long been at the core of antiviral drug development and this review illustrates different molecular strategies by which NNAs inhibit viral infection. Highlighting well-known as well as recent, clinically promising compounds, structural features and mechanistic details that may confer broad-spectrum activity are discussed. The final part addresses limitations of NNAs for clinical development such as low efficacy or mitochondrial toxicity and illustrates strategies to overcome these.

scholarly journals Sirtuins Are Evolutionarily Conserved Viral Restriction Factors

mBio ◽  
2014 ◽  
Vol 5 (6) ◽  
Author(s):  
Emre Koyuncu ◽  
Hanna G. Budayeva ◽  
Yana V. Miteva ◽  
Dante P. Ricci ◽  
Thomas J. Silhavy ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Rna Virus ◽  
Immune Defense ◽  
Human Pathogens ◽  
Activity Increase ◽  
Virus Growth ◽  
Cell Defense ◽  
Influenza A H1n1 ◽  
Evolutionarily Conserved

ABSTRACTThe seven human sirtuins are a family of ubiquitously expressed and evolutionarily conserved NAD+-dependent deacylases/mono-ADP ribosyltransferases that regulate numerous cellular and organismal functions, including metabolism, cell cycle, and longevity. Here, we report the discovery that all seven sirtuins have broad-range antiviral properties. We demonstrate that small interfering RNA (siRNA)-mediated knockdown of individual sirtuins and drug-mediated inhibition of sirtuin enzymatic activity increase the production of virus progeny in infected human cells. This impact on virus growth is observed for both DNA and RNA viruses. Importantly, sirtuin-activating drugs inhibit the replication of diverse viruses, as we demonstrate for human cytomegalovirus, a slowly replicating DNA virus, and influenza A (H1N1) virus, an RNA virus that multiplies rapidly. Furthermore, sirtuin defense functions are evolutionarily conserved, since CobB, the sirtuin homologue inEscherichia coli, protects against bacteriophages. Altogether, our findings establish sirtuins as broad-spectrum and evolutionarily conserved components of the immune defense system, providing a framework for elucidating a new set of host cell defense mechanisms and developing sirtuin modulators with antiviral activity.IMPORTANCEWe live in a sea of viruses, some of which are human pathogens. These pathogenic viruses exhibit numerous differences: DNA or RNA genomes, enveloped or naked virions, nuclear or cytoplasmic replication, diverse disease symptoms, etc. Most antiviral drugs target specific viral proteins. Consequently, they often work for only one virus, and their efficacy can be compromised by the rapid evolution of resistant variants. There is a need for the identification of host proteins with broad-spectrum antiviral functions, which provide effective targets for therapeutic treatments that limit the evolution of viral resistance. Here, we report that sirtuins present such an opportunity for the development of broad-spectrum antiviral treatments, since our findings highlight these enzymes as ancient defense factors that protect against a variety of viral pathogens.

scholarly journals Novel and potent inhibitors targeting DHODH, a rate-limiting enzyme in de novo pyrimidine biosynthesis, are broad-spectrum antiviral against RNA viruses including newly emerged coronavirus SARS-CoV-2

2020 ◽  
Author(s):  
Rui Xiong ◽  
Leike Zhang ◽  
Shiliang Li ◽  
Yuan Sun ◽  
Minyi Ding ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Ebola Virus ◽  
De Novo ◽  
Rna Viruses ◽  
Direct Acting Antiviral ◽  
Novel Coronavirus ◽  
Direct Acting ◽  
Viral Mutagenesis

AbstractEmerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of coronavirus SARS-CoV-2. Existing direct-acting antiviral (DAA) drugs cannot be applied immediately to new viruses because of virus-specificity, and the development of new DAA drugs from the beginning is not timely for outbreaks. Thus, host-targeting antiviral (HTA) drugs have many advantages to fight against a broad spectrum of viruses, by blocking the viral replication and overcoming the potential viral mutagenesis simultaneously. Herein, we identified two potent inhibitors of DHODH, S312 and S416, with favorable drug-like and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus (H1N1, H3N2, H9N2), Zika virus, Ebola virus, and particularly against the recent novel coronavirus SARS-CoV-2. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knocking-out cells. We also proposed the drug combination of DAA and HTA was a promising strategy for anti-virus treatment and proved that S312 showed more advantageous than Oseltamivir to treat advanced influenza diseases in severely infected animals. Notably, S416 is reported to be the most potent inhibitor with an EC50 of 17nM and SI value >5882 in SARS-CoV-2-infected cells so far. This work demonstrates that both our self-designed candidates and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-repression may have clinical potentials not only to influenza but also to COVID-19 circulating worldwide, no matter such viruses mutate or not.

scholarly journals Targeting the DEAD-box RNA Helicase eIF4A with Rocaglates - A Pan-Antiviral Strategy for Minimizing the Impact of Future RNA Virus Pandemics

2021 ◽  
Author(s):  
Gaspar Taroncher-Oldenburg ◽  
Christin Müller ◽  
Wiebke Obermann ◽  
John Ziebuhr ◽  
Roland K. Hartmann ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Rna Viruses ◽  
Rna Virus ◽  
Rna Helicase ◽  
Inhibitory Effect ◽  
Viral Mrnas ◽  
Eukaryotic Translation ◽  
Dead Box ◽  
A Minor ◽  
The Impact

The increase in pandemics caused by RNA viruses of zoonotic origin highlights the urgent need for broad-spectrum antivirals against novel and re-emerging RNA viruses. Broad-spectrum antivirals could be deployed as first-line interventions during an outbreak while virus-specific drugs and vaccines are developed and rolled out. Viruses depend on the host’s protein synthesis machinery for replication. Several natural compounds that target the cellular DEAD-box RNA helicase eIF4A, a key component of the eukaryotic translation initiation complex eIF4F, have emerged as potential broad-spectrum antivirals. Rocaglates, a group of flavaglines of plant origin that clamp mRNAs with highly structured 5’UTRs onto the surface of eIF4A through specific stacking interactions, exhibit the largest selectivity and potential therapeutic indices among all known eIF4A inhibitors. Their unique mechanism of action limits the inhibitory effect of rocaglates to the translation of eIF4A-dependent viral mRNAs and a minor fraction of host mRNAs exhibiting stable RNA secondary structures and/or polypurine sequence stretches in their 5´UTRs, resulting in minimal potential toxic side effects. Maintaining a favorable safety profile while inducing efficient inhibition of a broad-spectrum of RNA viruses makes rocaglates into primary candidates for further development as pan-antiviral therapeutics.

scholarly journals 4′-Fluorouridine is an oral antiviral that blocks respiratory syncytial virus and SARS-CoV-2 replication

Science ◽  
2022 ◽  
Vol 375 (6577) ◽  
pp. 161-167
Author(s):  
Julien Sourimant ◽  
Carolin M. Lieber ◽  
Megha Aggarwal ◽  
Robert M. Cox ◽  
Josef D. Wolf ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Severe Acute Respiratory Syndrome ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Antiviral Drugs ◽  
Emerging Pathogens ◽  
Primary Indication ◽  
Syncytial Virus ◽  
Derivatives Of

Preparing antiviral defenses Antiviral drugs are an important tool in the battle against COVID-19. Both remdesivir and molnupiravir, which target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase, were first developed against other RNA viruses. This highlights the importance of broad-spectrum antivirals that can be rapidly deployed against related emerging pathogens. Sourimant et al . used respiratory syncytial virus (RSV) as a primary indication in identifying further drugs that target the polymerase enzyme of RNA viruses. The authors explored derivatives of molnupiravir and identified 4′ fluorouridine (EIDD-2749) as an inhibitor of the polymerase of RSV and SARS-CoV-2. This drug can be delivered orally and was effective against RSV in mice and SARS-CoV-2 in ferrets. —VV

scholarly journals Predicting Broad-Spectrum Antiviral Drugs against RNA Viruses Using Transcriptional Responses to Exogenous RNA

2021 ◽  
Author(s):  
Akpeli V. Nordor ◽  
Geoffrey H. Siwo
Keyword(s):  
Antiviral Activity ◽  
Small Molecules ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Antiviral Drugs ◽  
Viral Rna ◽  
Host Cells ◽  
Target Cells ◽  
Transcriptional Responses ◽  
Exogenous Rna

All RNA viruses deliver their genomes into target host cells through processes distinct from normal trafficking of cellular RNA transcripts. The delivery of viral RNA into most cells hence triggers innate antiviral defenses that recognize viral RNA as foreign. In turn, viruses have evolved mechanisms to subvert these defenses, allowing them to thrive in target cells. Therefore, drugs activating defense to exogenous RNA could serve as broad-spectrum antiviral drugs. Here we show that transcriptional signatures associated with cellular responses to the delivery of a non-viral exogenous RNA sequence into human cells predict small molecules with broad-spectrum antiviral activity. In particular, transcriptional responses to the delivery of Cas9 mRNA into human hematopoietic stem and progenitor cells (HSPCs) highly matches those triggered by small molecules with broad-spectrum antiviral activity such as emetine, homoharringtonine, pyrvinium pamoate and anisomycin, indicating that these drugs are potentially active against other RNA viruses. Furthermore, these drugs have been approved for other indications and could thereby be repurposed to novel viruses. We propose that the antiviral activity of these drugs to SARS-CoV-2 should therefore be determined as they have been shown as active against other coronaviruses including SARS-CoV-1 and MERS-CoV. Indeed, two of these drugs- emetine and homoharringtonine- were independently shown to inhibit SARS-CoV-2 as this article was in preparation. These drugs could also be explored as potential adjuvants to COVID-19 vaccines in development due to their potential effect on the innate antiviral defenses that could bolster adaptive immunity when delivered alongside vaccine antigens.

scholarly journals Predicting Broad-Spectrum Antiviral Drugs against RNA Viruses Using Transcriptional Responses to Exogenous RNA

2020 ◽  
Author(s):  
Akpeli V. Nordor ◽  
Geoffrey H. Siwo
Keyword(s):  
Antiviral Activity ◽  
Small Molecules ◽  
Broad Spectrum ◽  
Rna Viruses ◽  
Antiviral Drugs ◽  
Viral Rna ◽  
Host Cells ◽  
Target Cells ◽  
Transcriptional Responses ◽  
Exogenous Rna

All RNA viruses deliver their genomes into target host cells through processes distinct from normal trafficking of cellular RNA transcripts. The delivery of viral RNA into most cells hence triggers innate antiviral defenses that recognize viral RNA as foreign. In turn, viruses have evolved mechanisms to subvert these defenses, allowing them to thrive in target cells. Therefore, drugs activating defense to foreign or exogenous RNA could serve as broad-spectrum antiviral drugs. Here we show that transcriptional signatures associated with cellular responses to the delivery of a non-viral exogenous RNA sequence into human cells predicts small molecules with broad-spectrum antiviral activity. In particular, transcriptional responses to the delivery of cas9 mRNA into human hematopoietic stem and progenitor cells (HSPCs) highly matches those triggered by small molecules with broad-spectrum antiviral activity such as emetine, homoharringtonine, pyrvinium pamoate and anisomycin, indicating that these drugs are potentially active against other RNA viruses. Furthermore, these drugs have been approved for other indications and could thereby be repurposed to novel viruses. We propose that the antiviral activity of these drugs to SARS-CoV-2 should therefore be determined as they have been shown as active against other coronaviruses including SARS-CoV and MERS-CoV. These drugs could also be explored as potential adjuvants to COVID-19 vaccines in development due to their potential effect on the innate antiviral defenses that could bolster adaptive immunity when delivered alongside vaccine antigens.

scholarly journals Zinc finger antiviral protein (ZAP) activity in mammalian and avian hosts in CpG and UpA-mediated restriction of RNA viruses and investigation of ZAP-mediated shaping of host transcriptome compositions

2021 ◽  
Author(s):  
Valerie Odon ◽  
Steven fiddaman ◽  
Adrian Smith ◽  
Peter Simmonds
Keyword(s):  
Cell Lines ◽  
Zinc Finger ◽  
Influenza A ◽  
Rna Viruses ◽  
Rna Virus ◽  
Virus Genome ◽  
Antiviral Protein ◽  
Cpg Dinucleotides ◽  
Antiviral State ◽  
Mammalian Cell Lines

The ability of zinc finger antiviral protein (ZAP) to recognise and respond to RNA virus sequences with elevated frequencies of CpG dinucleotides has been proposed as a functional part of the vertebrate innate immune antiviral response. It has been further proposed that ZAP activity shapes compositions of cytoplasmic mRNA sequences to avoid self-recognition, particularly mRNAs for interferons (IFNs) and IFN-stimulated genes highly expressed when ZAP is upregulated during the antiviral state. We investigated the ZAP functional activity in different species of mammals and birds, and potential downstream effects of differences in CpG and UpA dinucleotide representations in host transcriptomes and in RNA viruses that infect them. Cell lines from different bird orders showed variability in restriction of influenza A virus and echovirus 7 replicons with elevated CpG frequencies and none restricted UpA-high mutants, in marked contrast to mammalian cell lines. Given this variability, we compared CpG and UpA representation in coding regions of ISGs and IFNs with the total cellular transcriptome to determine whether differences in ZAP activity shaped dinucleotide compositions of highly expressed genes during the antiviral state. While type 1 IFN genes typically showed often profound suppression of CpG and UpA frequencies, there was no over-suppression of CpGs or UpAs in ISGs in any species, irrespective of underlying ZAP activity. Similarly, mammalian and avian RNA virus genome sequences were compositionally equivalent as were IAV serotypes recovered from ducks, chickens and humans. Overall, we found no evidence for host variability in ZAP function impacting compositions of antiviral genes.

scholarly journals A Novel Endonuclease Inhibitor Exhibits Broad-Spectrum Anti-Influenza Virus ActivityIn Vitro

2016 ◽  
Vol 60 (9) ◽  
pp. 5504-5514 ◽  
Author(s):  
Jeremy C. Jones ◽  
Bindumadhav M. Marathe ◽  
Christian Lerner ◽  
Lukas Kreis ◽  
Rodolfo Gasser ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Broad Spectrum ◽  
Influenza A ◽  
Mdck Cells ◽  
Influenza Virus Infection ◽  
Antiviral Drugs ◽  
Influenza Viruses ◽  
Yield Reduction ◽  
Genome Replication ◽  
Endonuclease Domain

ABSTRACTAntiviral drugs are important in preventing and controlling influenza, particularly when vaccines are ineffective or unavailable. A single class of antiviral drugs, the neuraminidase inhibitors (NAIs), is recommended for treating influenza. The limited therapeutic options and the potential risk of antiviral resistance are driving the search for additional small-molecule inhibitors that act on influenza virus proteins. The acid polymerase (PA) of influenza viruses is a promising target for new antivirals because of its essential role in initiating virus transcription. Here, we characterized a novel compound, RO-7, identified as a putative PA endonuclease inhibitor. RO-7 was effective when added before the cessation of genome replication, reduced polymerase activity in cell-free systems, and decreased relative amounts of viral mRNA and genomic RNA during influenza virus infection. RO-7 specifically inhibited the ability of the PA endonuclease domain to cleave a nucleic acid substrate. RO-7 also inhibited influenza A viruses (seasonal and 2009 pandemic H1N1 and seasonal H3N2) and B viruses (Yamagata and Victoria lineages), zoonotic viruses (H5N1, H7N9, and H9N2), and NAI-resistant variants in plaque reduction, yield reduction, and cell viability assays in Madin-Darby canine kidney (MDCK) cells with nanomolar to submicromolar 50% effective concentrations (EC50s), low toxicity, and favorable selective indices. RO-7 also inhibited influenza virus replication in primary normal human bronchial epithelial cells. Overall, RO-7 exhibits broad-spectrum activity against influenza A and B viruses in multiplein vitroassays, supporting its further characterization and development as a potential antiviral agent for treating influenza.

scholarly journals Novel and potent inhibitors targeting DHODH are broad-spectrum antivirals against RNA viruses including newly-emerged coronavirus SARS-CoV-2

2020 ◽  
Vol 11 (10) ◽  
pp. 723-739 ◽  
Author(s):  
Rui Xiong ◽  
Leike Zhang ◽  
Shiliang Li ◽  
Yuan Sun ◽  
Minyi Ding ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Influenza A ◽  
Ebola Virus ◽  
Rna Viruses ◽  
The Novel ◽  
Knock Out ◽  
Infected Cells ◽  
Virus Zika ◽  
Novel Coronavirus

Abstract Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC50 of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.

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