scholarly journals Recapitulating Trafficking of Nucleosides Into the Active Site of Polymerases of RNA Viruses: The Challenge and the Prize

2021 ◽  
Vol 3 ◽  
Author(s):  
Yves Boulard ◽  
Stéphane Bressanelli
Keyword(s):  
Hepatitis C ◽  
Active Site ◽  
Viral Infections ◽  
Rna Viruses ◽  
Early Stage ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Influenza Viruses ◽  
Human Pathogens ◽  
Hepatitis C Viruses

Nucleoside analogs are very effective antiviral agents with currently over 25 compounds approved for the therapy of viral infections. Still, their successful use against RNA viruses is very recent, despite RNA viruses comprising some of the most damaging human pathogens (e.g., Coronaviruses, Influenza viruses, or Flaviviridae such as dengue, Zika and hepatitis C viruses). The breakthrough came in 2013–2014, when the nucleoside analog Sofosbuvir became one of the cornerstones of current curative treatments for hepatitis C virus (HCV). An analog designed on the same principles, Remdesivir, has been the first approved compound against SARS-CoV-2, the coronavirus that causes the current COVID-19 pandemic. Both of these nucleoside analogs target the RNA-dependent RNA polymerase (RdRp) (NS5B for HCV, nsp12 for SARS-CoV-2). RdRps of RNA viruses display a peculiar elaboration of the classical polymerase architecture that leads to their active site being caged. Thus, triphosphate nucleosides and their analogs must access this active site in several steps along a narrow and dynamic tunnel. This makes straightforward computational approaches such as docking unsuitable for getting atomic-level details of this process. Here we give an account of ribose-modified nucleoside analogs as inhibitors of viral RdRps and of why taking into account the dynamics of these polymerases is necessary to understand nucleotide selection by RdRps. As a case study we use a computational protocol we recently described to examine the approach of the NTP tunnel of HCV NS5B by cellular metabolites of Sofosbuvir. We find major differences with natural nucleotides even at this early stage of nucleotide entry.

scholarly journals Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses

2019 ◽  
Vol 63 (7) ◽  
Author(s):  
Keivan Zandi ◽  
Leda Bassit ◽  
Franck Amblard ◽  
Bryan D. Cox ◽  
Pouya Hassandarvish ◽  
...  
Keyword(s):  
Japanese Encephalitis ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Public Health Problem ◽  
Nucleoside Analogs ◽  
Global Public Health ◽  
Direct Acting Antiviral ◽  
East And Southeast Asia ◽  
Direct Acting ◽  
Global Public Health Problem

ABSTRACTDengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from theFlaviviridaefamily. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world’s population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2′-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.

scholarly journals The experience of domestic antiviral agents, and some of own approaches in the treatment of chronic hepatitis C in adults

2015 ◽  
Vol 20 (3) ◽  
pp. 4-10
Author(s):  
V. A Borisov ◽  
B. I Sanin ◽  
S. E Samsonova ◽  
E. N Arutyunyan ◽  
D. B Golubeva ◽  
...  
Keyword(s):  
Chronic Hepatitis ◽  
Hepatitis C ◽  
Chronic Hepatitis C ◽  
Gradual Increase ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Antiviral Drugs ◽  
Weekly Dose ◽  
Glycyrrhizinic Acid ◽  
Cell Immunity

In the management of 148 adult patients with chronic hepatitis C (CHC) of both sexes without special selection (taken into account only absolute contraindications to its performance) there were used domestic basic antiviral drugs - BAD\ (short-living interferons (IFN) a, interferon inducers and nucleoside analogues) in parallel with additional antiviral drugs (drug glycyrrhizinic acid or amantadine) and maintenance therapy (stimulators of T-cell immunity and means of correction of side effects). Treatment was carried out in the framework of the developed complex of principles and approaches including in part, the formation of the starting average weekly dose of interferon IFN with accounting of the character of interferon status of the patient, a gradual increase in the average weekly dose of interferon IFN during the course of therapy, the delayed use of nucleoside analogs and others. As a result, against the background of a significant reduction in financial expenses and the aggressiveness of treatment the stable positive therapeutic outcome in the general population ofpatients occurred in 92.6%, with 87.2% in patients with genotype (G) 1.

scholarly journals Upstream translation initiation expands the coding capacity of segmented negative-strand RNA viruses

2019 ◽  
Author(s):  
Elizabeth Sloan ◽  
Marta Alenquer ◽  
Liliane Chung ◽  
Sara Clohisey ◽  
Adam M. Dinan ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Influenza A ◽  
Viral Infections ◽  
Rna Viruses ◽  
Influenza Viruses ◽  
Open Reading Frames ◽  
Viral Gene ◽  
Influenza A Viruses ◽  
Negative Strand ◽  
Coding Potential

AbstractSegmented negative-strand RNA viruses (sNSVs) include the influenza viruses, the bunyaviruses, and other major pathogens of humans, other animals and plants. The genomes of these viruses are extremely short. In response to this severe genetic constraint, sNSVs use a variety of strategies to maximise their coding potential. Because the eukaryotic hosts parasitized by sNSVs can regulate gene expression through low levels of translation initiation upstream of their canonical open reading frames (ORFs), we asked whether sNSVs could use upstream translation initiation to expand their own genetic repertoires. Consistent with this hypothesis, we showed that influenza A viruses (IAVs) and bunyaviruses were capable of upstream translation initiation. Using a combination of reporter assays and viral infections, we found that upstream translation in IAVs can initiate in two unusual ways: through non-AUG initiation in virally encoded ‘untranslated’ regions, and through the appropriation of an AUG-containing leader sequence from host mRNAs through viral cap-snatching, a process we termed ‘start-snatching.’ Finally, while upstream translation of cellular genes is mainly regulatory, for sNSVs it also has the potential to create novel viral gene products. If in frame with a viral ORF, this creates N-extensions of canonical viral proteins. If not, it allows the expression of cryptic overlapping ORFs, which we found were highly conserved in IAV and widely distributed in peribunyaviruses. Thus, by exploiting their host’s capacity for upstream translation initiation, sNSVs can expand still further the coding potential of their extremely compact RNA genomes.

scholarly journals Nucleotide Substrate Specificity of Anti-Hepatitis C Virus Nucleoside Analogs for Human Mitochondrial RNA Polymerase

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Maryam Ehteshami ◽  
Longhu Zhou ◽  
Sheida Amiralaei ◽  
Jadd R. Shelton ◽  
Jong Hyun Cho ◽  
...  
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Substrate Specificity ◽  
Rna Polymerase ◽  
Rna Virus ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Mitochondrial Rna ◽  
Mitochondrial Rna Polymerase

ABSTRACT Nucleoside analog inhibitors (NAIs) are an important class of antiviral agents. Although highly effective, some NAIs with activity against hepatitis C virus (HCV) can cause toxicity, presumably due to off-target inhibition of host mitochondrial RNA polymerase (POLRMT). The in vitro nucleotide substrate specificity of POLRMT was studied in order to explore structure-activity relationships that can facilitate the identification of nontoxic NAIs. These findings have important implications for the development of all anti-RNA virus NAIs.

Antiviral Drug Targets of Single-Stranded RNA Viruses Causing Chronic Human Diseases

2020 ◽  
Vol 21 (2) ◽  
pp. 105-124 ◽  
Author(s):  
Dhurvas Chandrasekaran Dinesh ◽  
Selvaraj Tamilarasan ◽  
Kaushik Rajaram ◽  
Evžen Bouřa
Keyword(s):  
Drug Targets ◽  
Viral Infections ◽  
Rna Viruses ◽  
Antiviral Agents ◽  
Protein Structures ◽  
Antiviral Drug ◽  
Three Dimensional ◽  
Data Bank ◽  
Chronic Infections ◽  
Immunodeficiency Syndrome

Ribonucleic acid (RNA) viruses associated with chronic diseases in humans are major threats to public health causing high mortality globally. The high mutation rate of RNA viruses helps them to escape the immune response and also is responsible for the development of drug resistance. Chronic infections caused by human immunodeficiency virus (HIV) and hepatitis viruses (HBV and HCV) lead to acquired immunodeficiency syndrome (AIDS) and hepatocellular carcinoma respectively, which are one of the major causes of human deaths. Effective preventative measures to limit chronic and re-emerging viral infections are absolutely necessary. Each class of antiviral agents targets a specific stage in the viral life cycle and inhibits them from its development and proliferation. Most often, antiviral drugs target a specific viral protein, therefore only a few broad-spectrum drugs are available. This review will be focused on the selected viral target proteins of pathogenic viruses containing single-stranded (ss) RNA genome that causes chronic infections in humans (e.g. HIV, HCV, Flaviviruses). In the recent past, an exponential increase in the number of available three-dimensional protein structures (>150000 in Protein Data Bank), allowed us to better understand the molecular mechanism of action of protein targets and antivirals. Advancements in the in silico approaches paved the way to design and develop several novels, highly specific small-molecule inhibitors targeting the viral proteins.

scholarly journals Synthesis of 4′-Substituted-2′-Deoxy-2′-α-Fluoro Nucleoside Analogs as Potential Antiviral Agents

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1258
Author(s):  
Mahesh Kasthuri ◽  
Chengwei Li ◽  
Kiran Verma ◽  
Olivia Ollinger Russell ◽  
Lyndsey Dickson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Respiratory Syncytial Virus ◽  
Hepatitis B ◽  
Antiviral Activity ◽  
Rna Viruses ◽  
Antiviral Agents ◽  
Nucleoside Analogs ◽  
Viral Diseases ◽  
Immunodeficiency Virus ◽  
Syncytial Virus

Nucleoside analogs are widely used for the treatment of viral diseases (Hepatitis B/C, herpes and human immunodeficiency virus, HIV) and various malignancies. ALS-8176, a prodrug of the 4′-chloromethyl-2′-deoxy-2′-fluoro nucleoside ALS-8112, was evaluated in hospitalized infants for the treatment of respiratory syncytial virus (RSV), but was abandoned for unclear reasons. Based on the structure of ALS-8112, a series of novel 4′-modified-2′-deoxy-2′-fluoro nucleosides were synthesized. Newly prepared compounds were evaluated against RSV, but also against a panel of RNA viruses, including Dengue, West Nile, Chikungunya, and Zika viruses. Unfortunately, none of the compounds showed marked antiviral activity against these viruses.

scholarly journals Reporter Replicons for Antiviral Drug Discovery against Positive Single-Stranded RNA Viruses

Viruses ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 598
Author(s):  
Rafaela S. Fernandes ◽  
Marjorie C. L. C. Freire ◽  
Renata V. Bueno ◽  
Andre S. Godoy ◽  
Laura H. V. G. Gil ◽  
...  
Keyword(s):  
Reverse Genetics ◽  
Viral Infections ◽  
Antiviral Agents ◽  
Antiviral Drug ◽  
Genetic Alterations ◽  
Human Pathogens ◽  
Direct Acting Antivirals ◽  
Virus West Nile ◽  
Screening And Identification ◽  
Direct Acting

Single-stranded positive RNA ((+) ssRNA) viruses include several important human pathogens. Some members are responsible for large outbreaks, such as Zika virus, West Nile virus, SARS-CoV, and SARS-CoV-2, while others are endemic, causing an enormous global health burden. Since vaccines or specific treatments are not available for most viral infections, the discovery of direct-acting antivirals (DAA) is an urgent need. Still, the low-throughput nature of and biosafety concerns related to traditional antiviral assays hinders the discovery of new inhibitors. With the advances of reverse genetics, reporter replicon systems have become an alternative tool for the screening of DAAs. Herein, we review decades of the use of (+) ssRNA viruses replicon systems for the discovery of antiviral agents. We summarize different strategies used to develop those systems, as well as highlight some of the most promising inhibitors identified by the method. Despite the genetic alterations introduced, reporter replicons have been shown to be reliable systems for screening and identification of viral replication inhibitors and, therefore, an important tool for the discovery of new DAAs.

scholarly journals To Assess the Prevalence Rate of Hepatitis C among the Solid Waste Handler in Selected Areas

2021 ◽  
pp. 383-387
Author(s):  
Mayur Wanjari ◽  
Deeplata Mendhe
Keyword(s):  
Hepatitis C ◽  
Solid Waste ◽  
Prevalence Rate ◽  
Viral Infections ◽  
Sampling Technique ◽  
Cross Sectional Study ◽  
Cross Sectional ◽  
Wide Range ◽  
Expected Outcome ◽  
Hepatitis C Viruses

Introduction: Solid waste handlers are subjected to a wide range of occupational hazards. Among these hazards is the infection from hepatitis A, B or C viruses (HAV, HBV or HCV). This relationship has been the study subject of many researchers around the world, given that the infection of hepatitis viruses is a significant cause of morbidity and a socio-economic burden.Viral hepatitis is a liver inflammation arising from viral infections. There are classes of viruses affecting the liver. The most popular forms are hepatitis B (HBV) and hepatitis C viruses (HCV). Objective: this study is planning to assess the prevalence rate of Hepatitis C among solid waste handlers in selected areas. Methodology: Cross-sectional study research designed will be used in this study conducted on a solid waste handler. The unlikely purposefully sampling technique was used to select a sample for this study to analyze the prevalence rate. The researcher's study included 100 population from the selected area and investigation of Hepatitis C will do at A.V.B.R.H Hospital Sawangi (M) Wardha. The population was selected according to inclusion and exclusion criteria. Expected Outcome: In this research study expected outcome is solid waste handlers are may be suffering from Hepatitis C because of their working pattern and environment. Conclusion: The conclusion will be drawn from the results.

scholarly journals Nucleosides for the treatment of respiratory RNA virus infections

2018 ◽  
Vol 26 ◽  
pp. 204020661876448 ◽  
Author(s):  
Paul C Jordan ◽  
Sarah K Stevens ◽  
Jerome Deval
Keyword(s):  
Respiratory Virus ◽  
Respiratory Infections ◽  
Rna Viruses ◽  
Rna Virus ◽  
Nucleoside Analogs ◽  
Respiratory Viruses ◽  
Influenza Viruses ◽  
Virus Infections ◽  
Nucleotide Analogs ◽  
Tract Infections

Influenza virus, respiratory syncytial virus, human metapneumovirus, parainfluenza virus, coronaviruses, and rhinoviruses are among the most common viruses causing mild seasonal colds. These RNA viruses can also cause lower respiratory tract infections leading to bronchiolitis and pneumonia. Young children, the elderly, and patients with compromised cardiac, pulmonary, or immune systems are at greatest risk for serious disease associated with these RNA virus respiratory infections. In addition, swine and avian influenza viruses, together with severe acute respiratory syndrome-associated and Middle Eastern respiratory syndrome coronaviruses, represent significant pandemic threats to the general population. In this review, we describe the current medical need resulting from respiratory infections caused by RNA viruses, which justifies drug discovery efforts to identify new therapeutic agents. The RNA polymerase of respiratory viruses represents an attractive target for nucleoside and nucleotide analogs acting as inhibitors of RNA chain synthesis. Here, we present the molecular, biochemical, and structural fundamentals of the polymerase of the four major families of RNA respiratory viruses: Orthomyxoviridae, Pneumoviridae/Paramyxoviridae, Coronaviridae, and Picornaviridae. We summarize past and current efforts to develop nucleoside and nucleotide analogs as antiviral agents against respiratory virus infections. This includes molecules with very broad antiviral spectrum such as ribavirin and T-705 (favipiravir), and others targeting more specifically one or a few virus families. Recent advances in our understanding of the structure(s) and function(s) of respiratory virus polymerases will likely support the discovery and development of novel nucleoside analogs.

The diagnosis of hepatitis C viral infection

2014 ◽  
Vol 155 (26) ◽  
pp. 1019-1023
Author(s):  
Judit Gervain
Keyword(s):  
Hepatitis C ◽  
Nucleic Acid ◽  
Viral Infection ◽  
Structural Changes ◽  
Viral Infections ◽  
Transient Elastography ◽  
Viral Nucleic Acid ◽  
Length Of Treatment ◽  
Subtype B

The successful therapy of hepatitis C viral infection requires that the illness is diagnosed before the development of structural changes of the liver. Testing is stepwise consisting of screening, diagnosis, and anti-viral therapy follow-up. For these steps there are different biochemical, serological, histological and molecular biological methods available. For screening, alanine aminotransferase and anti-HCV tests are used. The diagnosis of infection is confirmed using real-time polymerase chain reaction of the viral nucleic acid. Before initiation of the therapy liver biopsy is recommended to determine the level of structural changes in the liver. Alternatively, transient elastography or blood biomarkers may be also used for this purpose. Differential diagnosis should exclude the co-existence of other viral infections and chronic hepatitis due to other origin, with special attention to the presence of autoantibodies. The outcome of the antiviral therapy and the length of treatment are mainly determined by the viral genotype. In Hungary, most patients are infected with genotype 1, subtype b. The polymorphism type that occurs in the single nucleotide located next to the interleukin 28B region in chromosome 19 and the viral polymorphism type Q80K for infection with HCV 1a serve as predictive therapeutic markers. The follow-up of therapy is based on the quantitative determination of viral nucleic acid according to national and international protocols and should use the same method and laboratory throughout the treatment of an individual patient. Orv. Hetil., 2014, 155(26), 1019–1023.

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