Respiratory Syncytial Virus Disease: Prevention and Treatment

Chu, Helen Y.; Englund, Janet A.

doi:10.1007/978-3-642-38919-1_12

Cited by 21 publications

(23 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Significant efforts to develop a safe and effective vaccine against RSV are ongoing, but this has proven difficult, and currently none is licensed (4,5). The only effective antiviral drug is palizivumab, a humanized monoclonal antibody against the viral fusion protein, but this drug is costly and effective only if administered prophylactically (6). Currently there are no licensed, effective antiviral treatments.…”

mentioning

confidence: 99%

Respiratory Syncytial Virus Inhibitor AZ-27 Differentially Inhibits Different Polymerase Activities at the Promoter

Noton

Nagendra

Dunn

et al. 2015

J Virol

View full text Add to dashboard Cite

Respiratory syncytial virus (RSV) isIn this study, we examined the effect of AZ-27 on different aspects of RSV polymerase activity. AZ-27 was found to inhibit equally both mRNA transcription and genome replication in cell-based minigenome assays, indicating that it inhibits a step common to both of these RNA synthesis processes. Analysis in an in vitro transcription run-on assay, containing RSV nucleocapsids, showed that AZ-27 inhibits synthesis of transcripts from the 3= end of the genome to a greater extent than those from the 5= end, indicating that it inhibits transcription initiation. Consistent with this finding, experiments that assayed polymerase activity on the promoter showed that AZ-27 inhibited transcription and replication initiation. The RSV polymerase also can utilize the promoter sequence to perform a back-priming reaction. Interestingly, addition of AZ-27 had no effect on the addition of up to three nucleotides by back-priming but inhibited further extension of the backprimed RNA. These data provide new information regarding the mechanism of inhibition by AZ-27. They also suggest that the RSV polymerase adopts different conformations to perform its different activities at the promoter. -14), but its inhibitory mechanism was unknown. Understanding this would be valuable both for characterizing the polymerase and for further development of inhibitors. Here, we show that AZ-27 inhibits an early stage in mRNA transcription, as well as genome replication, by inhibiting initiation of RNA synthesis from the promoter. However, the compound does not inhibit back priming, another RNA synthesis activity of the RSV polymerase. These findings provide insight into the different activities of the RSV polymerase and will aid further development of antiviral agents against RSV. W orldwide, respiratory syncytial virus (RSV) is the major cause of respiratory disease in infants under the age of one, and it is the leading cause of infant hospitalization in the United States (1, 2). RSV also is recognized as a significant cause of morbidity and mortality in the elderly (3). Significant efforts to develop a safe and effective vaccine against RSV are ongoing, but this has proven difficult, and currently none is licensed (4, 5). The only effective antiviral drug is palizivumab, a humanized monoclonal antibody against the viral fusion protein, but this drug is costly and effective only if administered prophylactically (6). Currently there are no licensed, effective antiviral treatments. However, studies in human subjects showed that there is a correlation between virus load and disease severity, suggesting that administration of effective RSV inhibitors early in the disease course would reduce morbidity (7-9), and a recent human trial of a candidate RSV drug confirmed that a small-molecule inhibitor of viral replication ameliorated RSV-induced disease (10). Thus, there is a window during infection in which it is possible to treat RSV with antiviral drugs. This highlights the need to develop a detailed understan...

show abstract

mentioning

confidence: 99%

Respiratory Syncytial Virus Inhibitor AZ-27 Differentially Inhibits Different Polymerase Activities at the Promoter

Noton

Nagendra

Dunn

et al. 2015

J Virol

View full text Add to dashboard Cite

show abstract

“…Both the His-tag antigen and bumblebee total protein western Blot demonstrated that the polyclonal antibody was effective and specific to SMPD protein. Generally, the specificity of this kind of polyclonal antibody has been found to be lower than the monoclonal antibody (Chu & Englund, 2013). However, our Western blots suggested that the specificity of this kind was higher than expected which may require using a Eu-labeled goat anti-mouse kit which also could improve sensitivity and reduce background to guaranty higher blotting quality (Park et al, 2015;Lynch et al, 2016).…”

Section: Expression Characteristics Of Smpd In Bumblebeementioning

confidence: 65%

First Characterization of Sphingomyeline Phosphodiesterase Expression in the Bumblebee, Bombus lantschouensis

Han

Dong

et al. 2017

Sociobiology

View full text Add to dashboard Cite

The bumblebee (Bombus lantschouensis Vogt) is an important pollinator of wild plants. Sphingomyelin phosphodiesterase (SMPD) is a hydrolase that plays a major role in sphingolipid metabolism reactions. We report the preparation and characterization of a polyclonal antibody for bumblebee SMPD. We then use the polyclonal antiserum to detect the SMPD protein at different development stages and in different tissues. Our results showed that a 1228bp fragment homologous with the B. terrestris SMPD gene was successfully amplified. The molecular weight of the fusion protein was about 70 kDa by SDS-PAGE. An effective polyclonal antibody against SMPD was also obtained from mice and found to have a higher specificity for bumblebee SMPD. Western blotting detection showed that SMPD was expressed at a high level in queen ovaries, although expression was lower in the midgut and venom gland. SMPD expression decreased from the egg stage until the pdd stage. We interpret our results as showing that the development of an effective polyclonal antiserum for the SMPD protein of a bumblebee, which provides a tool for exploring the function of the SMPD gene. In addition, the work has confirmed that SMPD should be considered as an important enzyme during bumblebee egg and larval stages.

show abstract

“…The antiviral drug ribavirin was developed for the treatment of respiratory syncytial virus in symptomatic infants and was cleared by the FDA in 1986, 1 and although this medication was initially promising, it failed to have any significant impact on mortality or hospital duration in this population. 2 Despite the disappointing results of earlier studies, ribavirin has been shown to be an important treatment option in the management of respiratory syncytial virus infections in adult and pediatric patients with immunocompromised conditions associated with solid-organ and hematopoietic stem cell transplantation.…”

Section: Introductionmentioning

confidence: 99%

“…3 It has been shown to be effective at halting the progression of infection from the upper to the lower respiratory tract and at reducing the associated morbidity and mortality. 1 …”

Section: Introductionmentioning

confidence: 99%

Characterization of Ribavirin Aerosol With Small Particle Aerosol Generator and Vibrating Mesh Micropump Aerosol Technologies

et al. 2016

View full text Add to dashboard Cite

BACKGROUND: Ribavirin is an antiviral drug that can be administered by inhalation. Despite advancements in the oral delivery of this medication, there has been a renewed interested in delivering ribavirin via the pulmonary system. Although data are not conclusive that inhaled ribavirin improves outcomes, we set out to determine whether delivery by a newer generation nebulizer, the vibrating mesh micropump, was as effective as the recommended small-particle aerosol generator system. METHODS: We compared the physicochemical makeup and concentrations of ribavirin before and after nebulization with 0.9% NaCl and sterile water. An Andersen cascade impactor was used to determine particle size distribution and mass median aerodynamic diameter, and an absolute filter was used to measure total aerosol emitted output and inhaled dose during mechanical ventilation and spontaneous breathing. Ribavirin was analyzed and quantified using high-performance liquid chromatography with tandem mass spectrometric detection. RESULTS: Ribavirin was found to be stable in both 0.9% aqueous NaCl and sterile water with an r 2 value of 0.96 and identical coefficients of variation with no difference in drug concentration before and after nebulization with the vibrating mesh micropump. The small-particle aerosol generator produced a smaller mass median aerodynamic diameter (1.84 m) than the vibrating mesh micropump (3.63 m, P ‫؍‬ .02); however, there was no significant difference in the proportion of drug mass in the 0.7-4.7-m particle range. Total drug delivery was similar with the smallparticle aerosol generator and vibrating mesh micropump in both spontaneously breathing (P ‫؍‬ .77) and mechanical ventilation (P ‫؍‬ .48) models. CONCLUSIONS: The vibrating mesh micropump nebulizer may provide an effective alternative to the small-particle aerosol generator in administration of ribavirin using NaCl or sterile water, both on and off the ventilator. Further clinical studies are needed to compare efficacy.

show abstract

Respiratory Syncytial Virus Disease: Prevention and Treatment

Cited by 21 publications

References 80 publications

Respiratory Syncytial Virus Inhibitor AZ-27 Differentially Inhibits Different Polymerase Activities at the Promoter

Respiratory Syncytial Virus Inhibitor AZ-27 Differentially Inhibits Different Polymerase Activities at the Promoter

First Characterization of Sphingomyeline Phosphodiesterase Expression in the Bumblebee, Bombus lantschouensis

Characterization of Ribavirin Aerosol With Small Particle Aerosol Generator and Vibrating Mesh Micropump Aerosol Technologies

Contact Info

Product

Resources

About