scholarly journals Dengue Virus Reporter Replicon is a Valuable Tool for Antiviral Drug Discovery and Analysis of Virus Replication Mechanisms

Viruses ◽  
2016 ◽  
Vol 8 (5) ◽  
pp. 122 ◽  
Author(s):  
Fumihiro Kato ◽  
Takayuki Hishiki
Keyword(s):  
Drug Discovery ◽  
Dengue Virus ◽  
Virus Replication ◽  
Antiviral Drug

scholarly journals Phylogenetically based establishment of a dengue virus panel, representing all available genotypes, as a tool in dengue drug discovery

2018 ◽  
Author(s):  
Franck Touret ◽  
Cécile Baronti ◽  
Olivia Goethals ◽  
Marnix Van Loock ◽  
Xavier de Lamballerie ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Dengue Virus ◽  
Antiviral Drug ◽  
Genotypic Diversity ◽  
Genetic System ◽  
Reverse Genetic System ◽  
Amino Acid Homology ◽  
Dengue Viruses ◽  
Inhibitory Compounds ◽  
Arbovirus Diseases

AbstractDengue fever is the most widespread of the human arbovirus diseases, with approximately one third of the world’s population at risk of infection. Dengue viruses are members of the genus Flavivirus (family Flaviviridae) and, antigenically, they separate as four closely related serotypes (1-4) that share 60 to 75 % amino acid homology. This genetic diversity complicates the process of antiviral drug discovery. Thus, currently no approved dengue-specific therapeutic treatments are available. With the aim of providing an efficient tool for dengue virus drug discovery, a collection of nineteen dengue viruses, representing the genotypic diversity within the four serotypes, was developed. After phylogenetic analysis of the full-length genomes, we selected relevant strains from the EVAg collection at Aix-Marseille University and completed the virus collection, using a reverse genetic system based on the infectious sub-genomic amplicons technique. Finally, we evaluated this dengue virus collection against three published dengue inhibitory compounds. NITD008, which targets the highly conserved active site of the viral NS5 polymerase enzyme, exhibited similar antiviral potencies against each of the different dengue genotypes in the panel. Compounds targeting less conserved protein subdomains, such as the capsid inhibitor ST-148, or SDM25N, a ∂ opioid receptor antagonist which indirectly targets NS4B, exhibited larger differences in potency against the various genotypes of dengue viruses. These results illustrate the importance of a phylogenetically based dengue virus reference panel for dengue antiviral research. The collection developed in this study, which includes such representative dengue viruses, has been made available to the scientific community through the European Virus Archive to evaluate novel DENV antiviral candidates.

Thiosemicarbazides: Updates on antivirals strategy

2020 ◽  
Vol 20 ◽  
Author(s):  
Alok Kumar Moharana ◽  
Rudra Narayan Dash ◽  
Bharat Bhusan Subudhi
Keyword(s):  
Drug Discovery ◽  
Dengue Virus ◽  
Metal Complex ◽  
Viral Infection ◽  
Japanese Encephalitis Virus ◽  
Chikungunya Virus ◽  
Antiviral Drug ◽  
Safety And Efficacy ◽  
Drying Up ◽  
Emergence Of Resistance

: The challenges of viral infection have increased in recent decades due to the emergence of resistance, crossresistance and drying up of antiviral drug discovery. Many neglected tropical viruses including the chikungunya virus, dengue virus & Japanese encephalitis virus have gradually become global pathogens. This has further increased the burden of viral infection which necessitates the continuous development of antiviral therapy. The antiviral chemistry began with the development of thiosemicarbazide derived thiosemicarbazones as antiviral. Although very few thiosemicarbazides have progressed into clinical application, it still inspires antiviral development. During last 3 decades (1990-2020), several efforts have been made to develop suitable antiviral by using thiosemicarbazide scaffold. Its hybridization with other pharmacophores has been used as a strategy to enhance safety and efficacy. Cyclization and substitution of thiosemicarbazides have also been used to develop potent antiviral. With the ability to form coordinate bonds, thiosemicarbazides have been used either as metal complex or chelator against viruses. This work is an attempt to systematically review the research on the use of thiosemicarbazides as an antiviral scaffold. It also reviews the structureactivity relationship and translational suitability of thiosemicarbazide derived compounds.

scholarly journals Recent discoveries of influenza A drug target sites to combat virus replication

2016 ◽  
Vol 44 (3) ◽  
pp. 932-936 ◽  
Author(s):  
Hershna Patel ◽  
Andreas Kukol
Keyword(s):  
Drug Discovery ◽  
Virus Replication ◽  
Binding Sites ◽  
Drug Target ◽  
Influenza A ◽  
Antiviral Drug ◽  
Virus Transmission ◽  
Computational Tools ◽  
Sequence Variations ◽  
Target Sites

Sequence variations in the binding sites of influenza A proteins are known to limit the effectiveness of current antiviral drugs. Clinically, this leads to increased rates of virus transmission and pathogenicity. Potential influenza A inhibitors are continually being discovered as a result of high-throughput cell based screening studies, whereas the application of computational tools to aid drug discovery has further increased the number of predicted inhibitors reported. This review brings together the aspects that relate to the identification of influenza A drug target sites and the findings from recent antiviral drug discovery strategies.

scholarly journals Escape Mutations in NS4B Render Dengue Virus Insensitive to the Antiviral Activity of the Paracetamol Metabolite AM404

2016 ◽  
Vol 60 (4) ◽  
pp. 2554-2557 ◽  
Author(s):  
Koen W. R. van Cleef ◽  
Gijs J. Overheul ◽  
Michael C. Thomassen ◽  
Jenni M. Marjakangas ◽  
Ronald P. van Rij
Keyword(s):  
Antiviral Activity ◽  
Drug Development ◽  
Dengue Virus ◽  
Virus Replication ◽  
Disease Burden ◽  
Antiviral Drug ◽  
Virus Infections ◽  
Antiviral Compounds

ABSTRACTDespite the enormous disease burden associated with dengue virus infections, a licensed antiviral drug is lacking. Here, we show that the paracetamol (acetaminophen) metabolite AM404 inhibits dengue virus replication. Moreover, we find that mutations in NS4B that were previously found to confer resistance to the antiviral compounds NITD-618 and SDM25N also render dengue virus insensitive to AM404. Our work provides further support for NS4B as a direct or indirect target for antiviral drug development.

scholarly journals Structure-Based Design of Antivirals against Envelope Glycoprotein of Dengue Virus

Viruses ◽  
2020 ◽  
Vol 12 (4) ◽  
pp. 367
Author(s):  
Mohd Ishtiaq Anasir ◽  
Babu Ramanathan ◽  
Chit Laa Poh
Keyword(s):  
Drug Discovery ◽  
Dengue Virus ◽  
Structural Information ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Denv Infection ◽  
Antiviral Drugs ◽  
Global Public Health ◽  
Viral Attachment ◽  
E Protein

Dengue virus (DENV) presents a significant threat to global public health with more than 500,000 hospitalizations and 25,000 deaths annually. Currently, there is no clinically approved antiviral drug to treat DENV infection. The envelope (E) glycoprotein of DENV is a promising target for drug discovery as the E protein is important for viral attachment and fusion. Understanding the structure and function of DENV E protein has led to the exploration of structure-based drug discovery of antiviral compounds and peptides against DENV infections. This review summarizes the structural information of the DENV E protein with regards to DENV attachment and fusion. The information enables the development of antiviral agents through structure-based approaches. In addition, this review compares the potency of antivirals targeting the E protein with the antivirals targeting DENV multifunctional enzymes, repurposed drugs and clinically approved antiviral drugs. None of the current DENV antiviral candidates possess potency similar to the approved antiviral drugs which indicates that more efforts and resources must be invested before an effective DENV drug materializes.

scholarly journals Potential Phosphorylation of Viral Nonstructural Protein 1 in Dengue Virus Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1393
Author(s):  
Thanyaporn Dechtawewat ◽  
Sittiruk Roytrakul ◽  
Yodying Yingchutrakul ◽  
Sawanya Charoenlappanit ◽  
Bunpote Siridechadilok ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Nonstructural Protein ◽  
Antiviral Drug ◽  
Denv Infection ◽  
Site Directed Mutagenesis ◽  
Phosphorylation Sites ◽  
Post Translational Modification ◽  
Multifunctional Protein ◽  
Nonstructural Protein 1 ◽  
Underlying Mechanisms

Dengue virus (DENV) infection causes a spectrum of dengue diseases that have unclear underlying mechanisms. Nonstructural protein 1 (NS1) is a multifunctional protein of DENV that is involved in DENV infection and dengue pathogenesis. This study investigated the potential post-translational modification of DENV NS1 by phosphorylation following DENV infection. Using liquid chromatography-tandem mass spectrometry (LC-MS/MS), 24 potential phosphorylation sites were identified in both cell-associated and extracellular NS1 proteins from three different cell lines infected with DENV. Cell-free kinase assays also demonstrated kinase activity in purified preparations of DENV NS1 proteins. Further studies were conducted to determine the roles of specific phosphorylation sites on NS1 proteins by site-directed mutagenesis with alanine substitution. The T27A and Y32A mutations had a deleterious effect on DENV infectivity. The T29A, T230A, and S233A mutations significantly decreased the production of infectious DENV but did not affect relative levels of intracellular DENV NS1 expression or NS1 secretion. Only the T230A mutation led to a significant reduction of detectable DENV NS1 dimers in virus-infected cells; however, none of the mutations interfered with DENV NS1 oligomeric formation. These findings highlight the importance of DENV NS1 phosphorylation that may pave the way for future target-specific antiviral drug design.

New horizons for antiviral drug discovery from virus–host protein interaction networks

2012 ◽  
Vol 2 (5) ◽  
pp. 606-613 ◽  
Author(s):  
Benoît de Chassey ◽  
Laurène Meyniel-Schicklin ◽  
Anne Aublin-Gex ◽  
Patrice André ◽  
Vincent Lotteau
Keyword(s):  
Drug Discovery ◽  
Protein Interaction ◽  
Antiviral Drug ◽  
Protein Interaction Networks ◽  
Interaction Networks ◽  
Host Protein ◽  
New Horizons
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