scholarly journals Novel [(biphenyloxy)propyl]isoxazole derivatives for inhibition of human rhinovirus 2 and coxsackievirus B3 replication

2005 ◽  
Vol 55 (4) ◽  
pp. 483-488 ◽  
Author(s):  
Vadim A. Makarov ◽  
Olga B. Riabova ◽  
Vladimir G. Granik ◽  
Peter Wutzler ◽  
Michaela Schmidtke
Keyword(s):  
Coxsackievirus B3 ◽  
Human Rhinovirus ◽  
Isoxazole Derivatives

scholarly journals Direct and Indirect Effects on Viral Translation and RNA Replication Are Required for AUF1 Restriction of Enterovirus Infections in Human Cells

mBio ◽  
2018 ◽  
Vol 9 (5) ◽  
Author(s):  
Wendy Ullmer ◽  
Bert L. Semler
Keyword(s):  
Mrna Decay ◽  
Coxsackievirus B3 ◽  
Human Cells ◽  
Human Rhinovirus ◽  
Host Cells ◽  
Paralytic Poliomyelitis ◽  
Common Mechanism ◽  
Restriction Factor ◽  
Nucleocytoplasmic Trafficking ◽  
Viral Translation

ABSTRACTThe cellular mRNA decay protein AUF1 acts as a restriction factor during infection by picornaviruses, including poliovirus, coxsackievirus, and human rhinovirus. AUF1 relocalizes from the nucleus to the cytoplasm during infection by these viruses due to the disruption of nucleocytoplasmic trafficking by viral proteinases. Previous studies have demonstrated that AUF1 binds to poliovirus and coxsackievirus B3 (CVB3) RNA during infection, with binding shown to occur within the internal ribosome entry site (IRES) of the 5′ noncoding region (NCR) or the 3′ NCR, respectively. Binding to different sites within the viral RNA suggests that AUF1 may negatively regulate infection by these viruses using different mechanisms. The work presented here addresses the mechanism of AUF1 inhibition of the replication of poliovirus and CVB3. We demonstrate that AUF1 knockdown in human cells results in increased viral translation, RNA synthesis, and virus production. AUF1 is shown to negatively regulate translation of a poliovirus and CVB3 IRES reporter RNA during infection but not in uninfected cells. We found that this inhibitory activity is not mediated through destabilization of viral genomic RNA; however, it does require virus-induced relocalization of AUF1 from the nucleus to the cytoplasm during the early phases of infection. Our findings suggest that AUF1 restriction of poliovirus and CVB3 replication uses a common mechanism through the viral IRES, which is distinct from the canonical role that AUF1 plays in regulated mRNA decay in uninfected host cells.IMPORTANCEPicornaviruses primarily infect the gastrointestinal or upper respiratory tracts of humans and animals and may disseminate to tissues of the central nervous system, heart, skin, liver, or pancreas. Many common human pathogens belong to thePicornaviridaefamily, which includes viruses known to cause paralytic poliomyelitis (poliovirus); myocarditis (coxsackievirus B3 [CVB3]); the common cold (human rhinovirus [HRV]); and hand, foot, and mouth disease (enterovirus 71 [EV71]), among other illnesses. There are no specific treatments for infection, and vaccines exist for only two picornaviruses: poliovirus and hepatitis A virus. Given the worldwide distribution and prevalence of picornaviruses, it is important to gain insight into the host mechanisms used to restrict infection. Other than proteins involved in the innate immune response, few host factors have been identified that restrict picornavirus replication. The work presented here seeks to define the mechanism of action for the host restriction factor AUF1 during infection by poliovirus and CVB3.

scholarly journals Divergent Requirement for a DNA Repair Enzyme during Enterovirus Infections

mBio ◽  
2015 ◽  
Vol 7 (1) ◽  
Author(s):  
Sonia Maciejewski ◽  
Joseph H. C. Nguyen ◽  
Fernando Gómez-Herreros ◽  
Felipe Cortés-Ledesma ◽  
Keith W. Caldecott ◽  
...  
Keyword(s):  
Dna Repair ◽  
Viral Replication ◽  
Economic Impact ◽  
Coxsackievirus B3 ◽  
Replication Cycle ◽  
Human Rhinovirus ◽  
Paralytic Poliomyelitis ◽  
Protein Accumulation ◽  
Repair Enzyme ◽  
Potential Target

ABSTRACTViruses of theEnterovirusgenus of picornaviruses, including poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus, commandeer the functions of host cell proteins to aid in the replication of their small viral genomic RNAs during infection. One of these host proteins is a cellular DNA repair enzyme known as 5′ tyrosyl-DNA phosphodiesterase 2 (TDP2). TDP2 was previously demonstrated to mediate the cleavage of a unique covalent linkage between a viral protein (VPg) and the 5′ end of picornavirus RNAs. Although VPg is absent from actively translating poliovirus mRNAs, the removal of VPg is not required for thein vitrotranslation and replication of the RNA. However, TDP2 appears to be excluded from replication and encapsidation sites during peak times of poliovirus infection of HeLa cells, suggesting a role for TDP2 during the viral replication cycle. Using a mouse embryonic fibroblast cell line lacking TDP2, we found that TDP2 is differentially required among enteroviruses. Our single-cycle viral growth analysis shows that CVB3 replication has a greater dependency on TDP2 than does poliovirus or human rhinovirus replication. During infection, CVB3 protein accumulation is undetectable (by Western blot analysis) in the absence of TDP2, whereas poliovirus protein accumulation is reduced but still detectable. Using an infectious CVB3 RNA with a reporter, CVB3 RNA could still be replicated in the absence of TDP2 following transfection, albeit at reduced levels. Overall, these results indicate that TDP2 potentiates viral replication during enterovirus infections of cultured cells, making TDP2 a potential target for antiviral development for picornavirus infections.IMPORTANCEPicornaviruses are one of the most prevalent groups of viruses that infect humans and livestock worldwide. These viruses include the human pathogens belonging to theEnterovirusgenus, such as poliovirus, coxsackievirus B3 (CVB3), and human rhinovirus. Diseases caused by enteroviruses pose a major problem for public health and have significant economic impact. Poliovirus can cause paralytic poliomyelitis. CVB3 can cause hand, foot, and mouth disease and myocarditis. Human rhinovirus is the causative agent of the common cold, which has a severe economic impact due to lost productivity and severe health consequences in individuals with respiratory dysfunction, such as asthma. By gaining a better understanding of the enterovirus replication cycle, antiviral drugs against enteroviruses may be developed. Here, we report that the absence of the cellular enzyme TDP2 can significantly decrease viral yields of poliovirus, CVB3, and human rhinovirus, making TDP2 a potential target for an antiviral against enterovirus infections.

scholarly journals Antiviral activity of ginsenosides against coxsackievirus B3, enterovirus 71, and human rhinovirus 3

2014 ◽  
Vol 38 (3) ◽  
pp. 173-179 ◽  
Author(s):  
Jae-Hyoung Song ◽  
Hwa-Jung Choi ◽  
Hyuk-Hwan Song ◽  
Eun-Hye Hong ◽  
Bo-Ra Lee ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Enterovirus 71 ◽  
Coxsackievirus B3 ◽  
Human Rhinovirus

Hit QSAR Analysis of Anti-Coxsackievirus B3 Activity of [(Biphenyloxy)Propyl]Isoxazole Derivatives

2008 ◽  
Vol 78 (2) ◽  
pp. A60-A61 ◽  
Author(s):  
E. Muratov ◽  
V. Kuz’min ◽  
A. Artemenko ◽  
E. Varlamova ◽  
V. Makarov ◽  
...  
Keyword(s):  
Coxsackievirus B3 ◽  
Qsar Analysis ◽  
Isoxazole Derivatives

scholarly journals Amiloride Derivatives Inhibit Coxsackievirus B3 RNA Replication

2007 ◽  
Vol 82 (3) ◽  
pp. 1465-1473 ◽  
Author(s):  
David N. Harrison ◽  
Elena V. Gazina ◽  
Damian F. Purcell ◽  
David A. Anderson ◽  
Steven Petrou
Keyword(s):  
Amino Acid ◽  
Ion Channels ◽  
Antiviral Activity ◽  
Rna Replication ◽  
Viral Proteins ◽  
Coxsackievirus B3 ◽  
Human Rhinovirus ◽  
Amino Acid Substitutions ◽  
Intracellular Replication ◽  
Amiloride Derivatives

ABSTRACT Amiloride derivatives are known blockers of the cellular Na+/H+ exchanger and the epithelial Na+ channel. More recent studies demonstrate that they also inhibit ion channels formed by a number of viral proteins. We previously reported that 5-(N-ethyl-N-isopropyl)amiloride (EIPA) modestly inhibits intracellular replication and, to a larger extent, release of human rhinovirus 2 (HRV2) (E. V. Gazina, D. N. Harrison, M. Jefferies, H. Tan, D. Williams, D. A. Anderson and S. Petrou, Antiviral Res. 67:98-106, 2005). Here, we demonstrate that amiloride and EIPA strongly inhibit coxsackievirus B3 (CVB3) RNA replication and do not inhibit CVB3 release, in contrast to our previous findings on HRV2. Passaging of plasmid-derived CVB3 in the presence of amiloride generated mutant viruses with amino acid substitutions in position 299 or 372 of the CVB3 polymerase. Introduction of either of these mutations into the CVB3 plasmid produced resistance to amiloride and EIPA, suggesting that they act as inhibitors of CVB3 polymerase, a novel mechanism of antiviral activity for these compounds.

Successful in silico discovery of natural inhibitors for human rhinovirus coat protein

Planta Medica ◽  
2007 ◽  
Vol 73 (09) ◽  
Author(s):  
JM Rollinger ◽  
TM Steindl ◽  
K Anrain ◽  
EP Ellmerer ◽  
M Schmidtke ◽  
...  
Keyword(s):  
Coat Protein ◽  
In Silico ◽  
Human Rhinovirus ◽  
Natural Inhibitors
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