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

2021 ◽  
Vol 9 (3) ◽  
pp. 540
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′ untranslated regions (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 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 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.

Small-molecule inhibitors targeting eIF4A in leukemia

2021 ◽  
Vol 22 ◽  
Author(s):  
Xiaofeng Jia ◽  
Hong Zhou
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Tumor Therapy ◽  
Mrna Translation ◽  
Rna Helicase ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Eukaryotic Translation ◽  
Dead Box ◽  
Eukaryotic Translation Initiation

: Eukaryotic translation initiation factor 4A (eIF4A) is a highly conserved DEAD-box RNA helicase in eukaryotes with ATPase and RNA helicase activities. eIF4A plays an important role in cap-dependent translation at the initiation of mRNA translation, and carcinoma signal transduction pathways are focused on cap-dependent translation. eIF4A is highly expressed in a variety of cancers, and its high expression is associated with the degree of leukemia progression. Therefore, eIF4A, as a target for tumor therapy, has become a hot research topic. Many small-molecule inhibitors targeting eIF4A have been demonstrated in preclinical cancer model trials. The purpose of this review is to describe the function of eIF4A and the development of eIF4A targeting inhibitors.

scholarly journals Lethal Mutagenesis of Poliovirus Mediated by a Mutagenic Pyrimidine Analogue

2007 ◽  
Vol 81 (20) ◽  
pp. 11256-11266 ◽  
Author(s):  
Jason D. Graci ◽  
Daniel A. Harki ◽  
Victoria S. Korneeva ◽  
Jocelyn P. Edathil ◽  
Kathleen Too ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Mechanism Of Action ◽  
Rna Viruses ◽  
Rna Virus ◽  
Virus Titer ◽  
High Fidelity ◽  
Mutational Robustness ◽  
Lethal Mutagenesis ◽  
The Impact

ABSTRACT Lethal mutagenesis is the mechanism of action of ribavirin against poliovirus (PV) and numerous other RNA viruses. However, there is still considerable debate regarding the mechanism of action of ribavirin against a variety of RNA viruses. Here we show by using T7 RNA polymerase-mediated production of PV genomic RNA, PV polymerase-catalyzed primer extension, and cell-free PV synthesis that a pyrimidine ribonucleoside triphosphate analogue (rPTP) with ambiguous base-pairing capacity is an efficient mutagen of the PV genome. The in vitro incorporation properties of rPTP are superior to ribavirin triphosphate. We observed a log-linear relationship between virus titer reduction and the number of rPMP molecules incorporated. A PV genome encoding a high-fidelity polymerase was more sensitive to rPMP incorporation, consistent with diminished mutational robustness of high-fidelity PV. The nucleoside (rP) did not exhibit antiviral activity in cell culture, owing to the inability of rP to be converted to rPMP by cellular nucleotide kinases. rP was also a poor substrate for herpes simplex virus thymidine kinase. The block to nucleoside phosphorylation could be bypassed by treatment with the P nucleobase, which exhibited both antiviral activity and mutagenesis, presumably a reflection of rP nucleotide formation by a nucleotide salvage pathway. These studies provide additional support for lethal mutagenesis as an antiviral strategy, suggest that rPMP prodrugs may be highly efficacious antiviral agents, and provide a new tool to determine the sensitivity of RNA virus genomes to mutagenesis as well as interrogation of the impact of mutational load on the population dynamics of these viruses.

scholarly journals The GEF1 Proton-Chloride Exchanger Affects Tombusvirus Replication via Regulation of Copper Metabolism in Yeast

2012 ◽  
Vol 87 (3) ◽  
pp. 1800-1810 ◽  
Author(s):  
Zsuzsanna Sasvari ◽  
Nikolay Kovalev ◽  
Peter D. Nagy
Keyword(s):  
Rna Viruses ◽  
Rna Virus ◽  
Copper Metabolism ◽  
Inhibitory Effect ◽  
Cell Extract ◽  
Content Type ◽  
Direct Inhibitory Effect ◽  
Viral Replicase ◽  
Whole Plants

ABSTRACTReplication of plus-strand RNA viruses [(+)RNA viruses] is performed by viral replicases, whose function is affected by many cellular factors in infected cells. In this paper, we demonstrate a surprising role for Gef1p proton-chloride exchanger in replication ofTomato bushy stunt virus(TBSV) model (+)RNA virus. A genetic approach revealed that Gef1p, which is the only proton-chloride exchanger inSaccharomyces cerevisiae, is required for TBSV replication in the yeast model host. We also show that thein vitroactivity of the purified tombusvirus replicase fromgef1Δ yeast was low and that thein vitroassembly of the viral replicase in a cell extract was inhibited by the cytosolic fraction obtained fromgef1Δ yeast. Altogether, our data reveal that Gef1p modulates TBSV replication via regulating Cu2+metabolism in the cell. This conclusion is supported by several lines of evidence, including the direct inhibitory effect of Cu2+ions on thein vitroassembly of the viral replicase, on the activity of the viral RNA-dependent RNA polymerase, and an inhibitory effect of deletion ofCCC2copper pump on TBSV replication in yeast, while altered iron metabolism did not reduce TBSV replication. In addition, applying a chloride channel blocker impeded TBSV replication inNicotiana benthamianaprotoplasts or in whole plants. Overall, blocking Gef1p function seems to inhibit TBSV replication through altering Cu2+ion metabolism in the cytosol, which then inhibits the normal functions of the viral replicase.

Preliminary in Vitro Investigations on The Inhibitory Activity of The Original Dietary Supplement Oxidal® on Pathogenic Bacterial Strains

2020 ◽  
Vol 11 ◽  
pp. 37-43
Author(s):  
Prof. Teodora P. Popova ◽  
Toshka Petrova ◽  
Ignat Ignatov ◽  
Stoil Karadzhov
Keyword(s):  
Dietary Supplement ◽  
Broad Spectrum ◽  
Pathogenic Bacteria ◽  
Antimicrobial Agents ◽  
Clinical Effectiveness ◽  
Inhibitory Effect ◽  
Diffusion Method ◽  
Bacterial Strains ◽  
Microbial Strains

The antimicrobial action of the dietary supplement Oxidal® was tested using the classic Bauer and Kirby agar-gel diffusion method. Clinical and reference strains of Staphylococcus aureus and Escherichia coli were used in the studies. The tested dietary supplement showed a well-pronounced inhibitory effect against the microbial strains commensurable with that of the broad-spectrum chemotherapeutic agent Enrofloxacin and showed even higher activity than the broad spectrum antibiotic Thiamphenicol. The proven inhibitory effect of the tested dietary supplement against the examined pathogenic bacteria is in accordance with the established clinical effectiveness standards for antimicrobial agents.

Impact of Nanotechnology Patents on Green Development of China's Building Industry

2020 ◽  
Vol 14 (2) ◽  
pp. 141-152
Author(s):  
Xialing Sun ◽  
Rui Zhang ◽  
Xue Chen ◽  
Pengpeng Li ◽  
Jin Guo
Keyword(s):  
Total Factor Productivity ◽  
Inhibitory Effect ◽  
Building Industry ◽  
Factor Productivity ◽  
The Sustainable Development ◽  
Technological Support ◽  
Green Development ◽  
Panel Data Regression ◽  
The Impact ◽  
Building Engineering

Background: The sustainable development of the building industry has drawn increasing attention around the world. Nanomaterials and nanotechnology play an important role in the processes of energy saving and reducing consumption in the building industry. Nanotechnology patents provide key technological support for the green development of the building industry. Based on patent data in China, this paper quantitatively analyzed the application of nanotechnology patents in the building industry and the time trend, regional differences, and evolution of China's nano-patent applications in the building field. Methods: In this study, the environmental total factor productivity of the building industry considering carbon constraints was determined and then used as the dependent variable to measure the green development of the building industry. On this basis, a panel data regression model was constructed to determine the impact of nano-patents on the green development of the building industry. Results: Nanotechnology patents in the building industry can significantly improve total factor productivity. From the perspective of patent composition, technology-based patents that focus on substantial innovation can significantly promote the green development of the building industry, whereas strategic patents show a significant inhibitory effect. Regionally, the western region of China has the advantage of being less developed and thus more efficient than the central and eastern regions in the application of new nano-products. Finally, the research also showed a significant lag in the application of China's nanotechnology patents and low implementation efficiency. Conclusion: Nano patents can promote green development in the building industry, but there is room for improvement in the speed with which laboratory inventions are transformed into building engineering applications.

scholarly journals Structure Unveils Relationships between RNA Virus Polymerases

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 313
Author(s):  
Heli A. M. Mönttinen ◽  
Janne J. Ravantti ◽  
Minna M. Poranen
Keyword(s):  
Phylogenetic Tree ◽  
Rna Viruses ◽  
Rna Virus ◽  
Sequence Similarity ◽  
Protein Structures ◽  
Structural Similarity ◽  
Functional Differentiation ◽  
Comparison Method ◽  
Homologous Structure ◽  
Biological Entities

RNA viruses are the fastest evolving known biological entities. Consequently, the sequence similarity between homologous viral proteins disappears quickly, limiting the usability of traditional sequence-based phylogenetic methods in the reconstruction of relationships and evolutionary history among RNA viruses. Protein structures, however, typically evolve more slowly than sequences, and structural similarity can still be evident, when no sequence similarity can be detected. Here, we used an automated structural comparison method, homologous structure finder, for comprehensive comparisons of viral RNA-dependent RNA polymerases (RdRps). We identified a common structural core of 231 residues for all the structurally characterized viral RdRps, covering segmented and non-segmented negative-sense, positive-sense, and double-stranded RNA viruses infecting both prokaryotic and eukaryotic hosts. The grouping and branching of the viral RdRps in the structure-based phylogenetic tree follow their functional differentiation. The RdRps using protein primer, RNA primer, or self-priming mechanisms have evolved independently of each other, and the RdRps cluster into two large branches based on the used transcription mechanism. The structure-based distance tree presented here follows the recently established RdRp-based RNA virus classification at genus, subfamily, family, order, class and subphylum ranks. However, the topology of our phylogenetic tree suggests an alternative phylum level organization.

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