Natural Products as a Paradigm for the Treatment of Coxsackievirus - induced Myocarditis

2020 ◽  
Vol 20 (8) ◽  
pp. 607-616 ◽  
Author(s):  
Madhu Khanna ◽  
Anju Gautam ◽  
Roopali Rajput ◽  
Latika Sharma
Keyword(s):  
High Throughput Screening ◽  
Antiviral Agent ◽  
Viral Capsid ◽  
Specific Drug ◽  
Clinical Use ◽  
Infectious Agents ◽  
Nonstructural Proteins ◽  
Viral Proteases ◽  
Rna And Protein Synthesis ◽  
Molecular Libraries

Coxsackievirus B3 (CVB3), a member of the Picornaviridae family, is considered to be one of the most important infectious agents to cause virus-induced myocarditis. Despite improvements in studying viral pathology, structure and molecular biology, as well as diagnosis of this disease, there is still no virus-specific drug in clinical use. Structural and nonstructural proteins produced during the coxsackievirus life cycle have been identified as potential targets for blocking viral replication at the step of attachment, entry, uncoating, RNA and protein synthesis by synthetic or natural compounds. Moreover, WIN (for Winthrop) compounds and application of nucleic-acid based strategies were shown to target viral capsid, entry and viral proteases, but have not reached to the clinical trials as a successful antiviral agent. There is an urgent need for diverse molecular libraries for phenotype-selective and high-throughput screening.

scholarly journals Protease Inhibitors as Antiviral Agents

1998 ◽  
Vol 11 (4) ◽  
pp. 614-627 ◽  
Author(s):  
A. K. Patick ◽  
K. E. Potts
Keyword(s):  
Protease Inhibitors ◽  
Viral Infections ◽  
Critical Role ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Structural Proteins ◽  
Viral Protease ◽  
Virus Particles ◽  
Viral Proteases ◽  
Viral Polyprotein

SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

scholarly journals ORF1a-Encoded Replicase Subunits Are Involved in the Membrane Association of the Arterivirus Replication Complex

1998 ◽  
Vol 72 (8) ◽  
pp. 6689-6698 ◽  
Author(s):  
Yvonne van der Meer ◽  
Hans van Tol ◽  
Jacomine Krijnse Locker ◽  
Eric J. Snijder
Keyword(s):  
Equine Arteritis Virus ◽  
Viral Rna ◽  
Membrane Association ◽  
Nonstructural Proteins ◽  
Reading Frame ◽  
Replication Complex ◽  
Viral Proteases ◽  
Double Label ◽  
Membrane Bound ◽  
Triton X

ABSTRACT Among the functions of the replicase of equine arteritis virus (EAV; family Arteriviridae, order Nidovirales) are important viral enzyme activities such as proteases and the putative RNA polymerase and RNA helicase functions. The replicase is expressed in the form of two polyproteins (open reading frame 1a [ORF1a] and ORF1ab), which are processed into 12 nonstructural proteins by three viral proteases. In immunofluorescence assays, the majority of these cleavage products localized to the perinuclear region of the cell. A dense granular and vesicular staining was observed, which strongly suggested membrane association. By using confocal microscopy and double-label immunofluorescence, the distribution of the EAV replicase was shown to overlap with that of PDI, a resident protein of the endoplasmic reticulum and intermediate compartment. An in situ labeling of nascent viral RNA with bromo-UTP demonstrated that the membrane-bound complex in which the replicase subunits accumulate is indeed the site of viral RNA synthesis. A number of ORF1a-encoded hydrophobic domains were postulated to be involved in the membrane association of the arterivirus replication complex. By using various biochemical methods (Triton X-114 extraction, membrane purification, and sodium carbonate treatment), replicase subunits containing these domains were shown to behave as integral membrane proteins and to be membrane associated in infected cells. Thus, contribution to the formation of a membrane-bound scaffold for the viral replication-transcription complex appears to be an important novel function for the arterivirus ORF1a replicase polyprotein.

scholarly journals Identification and Characterization of New Inhibitors of the Escherichia coli MurA Enzyme

2001 ◽  
Vol 45 (11) ◽  
pp. 3182-3188 ◽  
Author(s):  
Ellen Z. Baum ◽  
Deborah A. Montenegro ◽  
Lisa Licata ◽  
Ignatius Turchi ◽  
Glenda C. Webb ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
High Throughput Screening ◽  
Chemical Library ◽  
Peptidoglycan Synthesis ◽  
Bacterial Enzyme ◽  
Purine Analog ◽  
Rna And Protein Synthesis ◽  
Molecular Modeling Studies ◽  
Identification And Characterization

ABSTRACT The bacterial enzyme MurA catalyzes the transfer of enolpyruvate from phosphoenolpyruvate (PEP) to uridine diphospho-N-acetylglucosamine (UNAG), which is the first committed step of bacterial cell wall biosynthesis. From high-throughput screening of a chemical library, three novel inhibitors of the Escherichia coli MurA enzyme were identified: the cyclic disulfide RWJ-3981, the purine analog RWJ-140998, and the pyrazolopyrimidine RWJ-110192. When MurA was preincubated with inhibitor, followed by addition of UNAG and PEP, the 50% inhibitory concentrations (IC50s) were 0.2 to 0.9 μM, compared to 8.8 μM for the known MurA inhibitor, fosfomycin. The three compounds exhibited MICs of 4 to 32 μg/ml against Staphylococcus aureus; however, the inhibition of DNA, RNA, and protein synthesis in addition to peptidoglycan synthesis by all three inhibitors indicated that antibacterial activity was not due specifically to MurA inhibition. The presence of UNAG during the MurA and inhibitor preincubation lowered the IC50 at least fivefold, suggesting that, like fosfomycin, the three compounds may interact with the enzyme in a specific fashion that is enhanced by UNAG. Ultrafiltration and mass spectrometry experiments suggested that the compounds were tightly, but not covalently, associated with MurA. Molecular modeling studies demonstrated that the compounds could fit into the site occupied by fosfomycin; exposure of MurA to each compound reduced the labeling of MurA by tritiated fosfomycin. Taken together, the evidence indicates that these inhibitors may bind noncovalently to the MurA enzyme, at or near the site where fosfomycin binds.

Detection of oncogenic viruses in water environments by a Luminex-based multiplex platform for high throughput screening of infectious agents

2017 ◽  
Vol 123 ◽  
pp. 549-555 ◽  
Author(s):  
P. Di Bonito ◽  
M. Iaconelli ◽  
T. Gheit ◽  
M. Tommasino ◽  
S. Della Libera ◽  
...  
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Infectious Agents ◽  
Oncogenic Viruses

scholarly journals Bloodborne Viral Pathogen Contamination in the Era of Laboratory Automation

2016 ◽  
Vol 62 (7) ◽  
pp. 973-981 ◽  
Author(s):  
Andrew Bryan ◽  
Linda Cook ◽  
Ederlyn E Atienza ◽  
Jane Kuypers ◽  
Anne Cent ◽  
...  
Keyword(s):  
Nucleic Acid ◽  
Risk Mitigation ◽  
Virus Disease ◽  
High Titer ◽  
Mitigation Strategies ◽  
Clinical Use ◽  
Infectious Agents ◽  
Laboratory Automation ◽  
Viral Pathogen ◽  
Viral Contamination

Abstract BACKGROUND The CDC states that laboratory testing for persons under investigation for Ebola virus disease can be safely performed using automated laboratory instruments by adhering to bloodborne pathogen practices. We therefore sought to investigate the levels of viral contamination of a total laboratory automation (TLA) system to guide risk mitigation strategies for handling infectious agents. METHODS Environmental swabs followed by PCR for hepatitis B (HBV) and hepatitis C (HCV) viruses were taken from a chemistry TLA system during routine clinical use and after running a small number of high-titer HCV samples. Control experiments were performed to ensure the recovery of DNA and RNA viruses by swabs from a representative nonporous surface. RESULTS Of 79 baseline swabs for nucleic acids performed on the TLA system, 10 were positive for HBV and 8 for HCV. Viral nucleic acid was consistently detected from swabs taken from the distal inside surface of the decapper discharge chute, with areas adjacent to the decapper instrument and the centrifuge rotor also positive for HBV or HCV nucleic acid. Contamination was occasionally detected on exposed surfaces in areas without protective barriers between samples and personnel. After running known HCV-positive samples, at least one additional site of contamination was detected on an exposed area of the line. CONCLUSIONS A low level of viral contamination of automated clinical laboratory equipment occurs in clinical use. Given the risks associated with highly infectious agents, there is a need for risk-mitigation procedures when handling all samples.

scholarly journals Where are all the new antibiotics? The new antibiotic paradox

2005 ◽  
Vol 16 (3) ◽  
pp. 159-160 ◽  
Author(s):  
JM Conly ◽  
BL Johnston
Keyword(s):  
North America ◽  
Infectious Diseases ◽  
20Th Century ◽  
Causes Of Death ◽  
Clinical Use ◽  
Infectious Agents ◽  
Antibiotic Development ◽  
Common Causes ◽  
New Antibiotics ◽  
The 1950S

At the beginning of the 20th century, illnesses caused by infectious agents ranked among the most common causes of death in North America and, indeed, worldwide. By the middle of the century, dramatic advances in the diagnosis, management and prevention of infectious diseases had occurred, and hopes were raised that many infectious diseases would be eliminated by the end of the 20th century. Much of this success in the management of infectious diseases was related to a continuous new armamentarium of antibiotics. The discovery of penicillin by Fleming in 1928 followed by the discovery and clinical use of sulphonamides in the 1930s heralded the age of modern antibiotherapy (1,2). Penicillin came into widespread use during the early 1940s. By the 1950s, the 'golden era' of antibiotic development and use was well underway, and multiple new classes of antibiotics were introduced over the next two decades (Table 1) (3).

Infectious antibodies in systemic lupus erythematosus patients

Lupus ◽  
2009 ◽  
Vol 18 (13) ◽  
pp. 1129-1135 ◽  
Author(s):  
Y. Berkun ◽  
G. Zandman-Goddard ◽  
O. Barzilai ◽  
M. Boaz ◽  
Y. Sherer ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Epstein Barr Virus ◽  
Viral Capsid ◽  
Infectious Agents ◽  
Viral Capsid Antigen ◽  
Igg Antibodies ◽  
Systemic Lupus ◽  
Early Antigen ◽  
Barr Virus ◽  
Epstein Barr

Infections can act as environmental triggers that induce or promote systemic lupus erythematosus (SLE) in genetically predisposed individuals. New technologies, developed recently, enable simultaneous assessment of multiple antibodies. Antibodies to specific infectious agents may shed light into the mechanisms of induction of SLE. The aim of this study was to investigate the prevalence of seropositivity and the titers of antibodies to bacterial, viral, and parasitic agents in SLE patients compared with non-autoimmune controls. Sera from 260 individuals (120 SLE patients and 140 controls) were tested by the BioPlex 2200 Multiplexed Immunoassay method (BioRad) for the prevalence and titers of antibodies to eight infectious agents (Epstein—Barr virus: early antigen IgG, nuclear antigen IgG, viral capsid antigen IgG and IgM, heterophile IgM; cytomegalovirus IgG and IgM; Toxoplasma gondii IgG and IgM; rubella IgG and IgM; Treponema pallidum TPr15G, TPr17G, TPr47G; herpes simplex virus type 1 and 2 IgG; hepatitis C virus and hepatitis B core antibodies. Cytomegalovirus IgM and Epstein—Barr virus early antigen IgG (but not other Epstein—Barr virus antigens) were significantly more prevalent in SLE patients than in controls. Conversely, positive titers of hepatitis B core and rubella IgG antibodies were less prevalent in the SLE patients than in controls. Other differences in titer positivity prevalence were not detected between patients and controls. The titers of the cytomegalovirus IgM, Toxoplasma IgG, Epstein—Barr virus early antigen, and viral capsid antigen IgG antibodies were significantly higher in SLE compared with controls. Our data suggest the importance of previous exposure to infectious agents in the induction and the prevention of SLE. Lupus (2009) 18, 1129—1135.

scholarly journals Has Ivermectin Virus-Directed Effects against SARS-CoV-2? Rationalizing the Action of a Potential Multitarget Antiviral Agent

2020 ◽  
Author(s):  
Antonio Francés-Monerris ◽  
Cristina Garcia-Iriepa ◽  
Isabel Iriepa ◽  
Cecilia Hognon ◽  
Tom Miclot ◽  
...  
Keyword(s):  
Wide Spectrum ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Host Immune System ◽  
Structural Protein ◽  
Cell Infection ◽  
Viral Proteases ◽  
Potent Inhibition ◽  
Dynamics Simulations

The novel SARS-CoV-2 coronavirus is causing a devastating pandemic in 2020, threatening public health in many countries. An unprecedented rapid and global response has been set in motion to identify efficient antiviral agents against SARS-CoV-2, mostly relying on the repurposing of drugs presenting or not previously known antiviral activity. Ivermectin is an approved drug used as antiparasitic in humans and animals with well documented broad-spectrum antiviral properties that emerge from host-directed effects. Recent results reported by Wagstaff and coworkers (Antiviral Research <b>2020</b>, <i>178</i>, 104787) show a potent inhibition of SARS-CoV-2 replication <i>in vitro </i>by ivermectin, and clinical trials with human volunteers have already started. However, the mode of action of ivermectin is still largely unknown, especially at the molecular level. Here, we employ advanced molecular dynamics simulations to assess the influence of ivermectin on several key viral protein targets, with the aim to reveal the molecular bases of antiviral mechanisms against SARS-CoV-2. Interestingly, we show that ivermectin could be regarded as a multitarget agent, inhibiting different viral functions. These include blocking the recognition by the SARS-CoV-2 Receptor Binding Domain (RBD) of the Angiotensin-Converting Enzyme 2 (ACE2), the interactions with the two viral proteases 3CL<sup>pro</sup> and PL<sup>pro</sup>, and the SARS Unique Domain (SUD) non-structural protein. Hence, the wide spectrum of actions involving i) the interference with cell infection, ii) the inhibition of viral replication, and iii) elusion of the host immune system, could point to an unprecedented synergy between host- and virus-directed effects explaining the high anti-SARS-CoV-2 activity observed for this compound.

Coumarins and Quinolones as Effective Multiple Targeted Agents Versus Covid-19: An in Silico Study

2021 ◽  
Vol 17 ◽  
Author(s):  
Mojgan Nejabat ◽  
Razieh Ghodsi ◽  
Farzin Hadizadeh
Keyword(s):  
Binding Affinity ◽  
In Silico ◽  
Oral Absorption ◽  
Antiviral Agent ◽  
In Vivo Studies ◽  
Reference Drug ◽  
Viral Proteases ◽  
In Silico Study

Background: The Covid-19 virus emerged a few months ago in China and infections rapidly escalated into a pandemic. Objective: To date, there is no selective antiviral agent for the management of pathologies associated with covid-19 and the need for an effective agent against it is essential. Method: In this work two home-made databases from synthetic quinolines and coumarins were virtually docked against viral proteases (3CL and PL), human cell surface proteases (TMPRSS2 and furin) and spike proteins (S1 and S2). Chloroquine, a reference drug without a clear mechanism against coronavirus was also docked on mentioned targets and the binding affinities compared with title compounds. Result: The best compounds of synthetic coumarins and quinolines for each target were determined. All compounds against all targets showed binding affinity between -5.80 to -8.99 kcal/mol in comparison with the FDA-approved drug, Chloroquine, with binding affinity of -5.7 to -7.98 kcal/mol. Two compounds, quinoline-1 and coumarin-24, were found to be effective on three targets – S2, TMPRSS2 and furin – simultaneously, with good predicted affinity between -7.54 to -8.85 kcal/mol. In silico ADME studies also confirmed good oral absorption for them. Furthermore, PASS prediction was calculated and coumarin-24 had higher probable activity (Pa) than probable inactivity (Pi) with acceptable protease inhibitory as well as good antiviral activity against Hepatitis C virus (HCV), Human immunodeficiency virus (HIV) and influenza. Conclusion: Quinoline-1 and Coumarin-24 have the potential to be used against Covid-19. Hence these agents could be useful in combating covid-19 infection after further in vitro and in vivo studies.

scholarly journals Detection of Nonstructural Protein 6 in Murine Coronavirus-Infected Cells and Analysis of the Transmembrane Topology by Using Bioinformatics and Molecular Approaches

2009 ◽  
Vol 83 (13) ◽  
pp. 6957-6962 ◽  
Author(s):  
Surendranath Baliji ◽  
Stephen A. Cammer ◽  
Bruno Sobral ◽  
Susan C. Baker
Keyword(s):  
Viral Replication ◽  
Hepatitis Virus ◽  
Nonstructural Protein ◽  
Nonstructural Proteins ◽  
Hydrophobic Domain ◽  
Transmembrane Topology ◽  
Molecular Approaches ◽  
Viral Proteases ◽  
Infected Cells ◽  
Membrane Spanning

ABSTRACT Coronaviruses encode large replicase polyproteins which are proteolytically processed by viral proteases to generate mature nonstructural proteins (nsps) that form the viral replication complex. Mouse hepatitis virus (MHV) replicase products nsp3, nsp4, and nsp6 are predicted to act as membrane anchors during assembly of the viral replication complexes. We report the first antibody-mediated Western blot detection of nsp6 from MHV-infected cells. The nsp6-specific peptide antiserum detected the replicase intermediate p150 (nsp4 to nsp11) and two nsp6 products of approximately 23 and 25 kDa. Analysis of nsp6 transmembrane topology revealed six membrane-spanning segments and a conserved hydrophobic domain in the C-terminal cytosolic tail.

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