Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: DrugBank:BIOD00097 (anti-RSV)
 466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Respiratory syncytial virus (RSV) is an important cause of severe lower respiratory tract illness in infants and the elderly. Presently, no safe and efficacious RSV vaccine exists; however, advances in our understanding of immunity and the pathogenesis of disease associated with RSV infection may lead to new vaccine strategies. RSV G protein contains a CX3C chemokine motif that interacts with the CX3CR1 chemokine receptor and modifies the activities of fractalkine. In the present study, we show that anti-RSV G protein antibody responses after recent RSV infection or vaccination are associated with inhibition of RSV G protein CX3C-CX3CR1 interaction and RSV G protein-mediated leukocyte chemotaxis.
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PMID:Anti-G protein antibody responses to respiratory syncytial virus infection or vaccination are associated with inhibition of G protein CX3C-CX3CR1 binding and leukocyte chemotaxis. 1552 57

(1) Respiratory syncytial virus (RSV) infection is common in infants; it is usually mild except in high risk children. (2) Palivizumab, a monoclonal antibody against RSV, was the first preventive treatment to be marketed in France. The licence was recently extended in France to cover children under 2 years of age who have haemodynamically significant congenital heart disease. (3) Follow-up data from Spanish cohorts of premature infants and infants with bronchopulmonary dysplasia are now available. The data tend to agree, albeit with different levels of evidence, that palivizumab reduces the risk of hospitalisation for RSV infection (3.95% of infants treated with palivizumab, 13.25% of untreated infants), but has no impact on the need for intensive care or on overall mortality. There are no data on the overall risk of hospitalisation. (4) In a randomised double-blind placebo-controlled trial in 1287 infants under 2 years of age with haemodynamically significant heart disease, palivizumab had no effect on mortality. But it did reduce the rate of hospitalisation both for RSV infection (5.3% versus 9.7%) and for all causes (54.9% versus 62.3%). (5) Few adverse effects have been reported after five years of use. The estimated risk of anaphylactic reactions is less than 1 per 100 000 infants. The risk of adverse effects when an infant is treated during a second season is poorly documented. (6) Treatment costs about 5000 euros per season for a 6 kg child. (7) In practice, palivizumab seems useful for the following categories of infants: those aged less than 6 months who were born with a gestational age of less than 32 weeks and who had bronchopulmonary dysplasia at birth; formerly premature infants under 2 years of age who are receiving long-term treatment for pulmonary sequelae; and infants with haemodynamically significant heart disease.
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PMID:Palivizumab: new indication. Moderate reduction in hospitalisation rate. 1561 42

We performed a large-scale random screening of an in-house chemical library based on the inhibition of respiratory syncytial virus (RSV)-induced cytopathic effect on HeLa (human cervical carcinoma) cells, and found a novel and specific anti-RSV agent, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403). YM-53403 potently inhibited the replication of RSV strains belonging to both A and B subgroups, but not influenza A virus, measles virus, or herpes simplex virus type 1. A plaque reduction assay was used to determine the 50% effective concentration (EC(50)) value for YM-53403. The value, 0.20 microM, was about 100-fold more potent than ribavirin. The result of a time-dependent drug addition test showed that YM-53403 inhibited the life cycle of RSV at around 8h post-infection, suggesting an inhibitory effect on early transcription and/or replication of the RSV genome. Consistent with this result, two YM-53403-resistant viruses have a single point mutation (Y1631H) in the L protein which is a RNA polymerase for both the transcription and replication of the RSV genome. YM-53403 is an attractive compound for the treatment of RSV infection because of its highly potent anti-RSV activity and the new mode of action, which differs from that of currently reported antiviral agents.
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PMID:YM-53403, a unique anti-respiratory syncytial virus agent with a novel mechanism of action. 1570 39

Palivizumab (PZ) is the only monoclonal antibody currently available for use in humans against an infectious disease. PZ is administered prophylactically for respiratory syncytial virus (RSV) infections. RSV selected in cell culture for growth in the presence of PZ develops F gene mutations and can be resistant to PZ prophylaxis in cotton rats. Here, we evaluated the potential for PZ-resistant RSV mutants to arise in vivo. Cotton rats were immunosuppressed with cyclophosphamide, administered PZ, and inoculated intranasally with RSV. Lungs were harvested 12 weeks after RSV infection, reverse transcription-PCR-amplified F gene fragments were cloned into plasmids, and the nucleotide sequences of the cloned cDNAs were determined. Three of the five animals had mixed populations of lung virus, and over 50% of the clones from the three animals revealed F gene mutations associated with resistance to PZ. A virus completely resistant to PZ neutralization was recovered from the lung homogenate of a rat that had received PZ. Thus, prolonged pulmonary replication of RSV in the presence of PZ was followed by the appearance of viruses resistant to PZ. The potential for the development of resistance is a consideration as the antibody is used prophylactically against RSV and as passively administered antibodies are under development for other infections, including emerging viruses and agents of biodefense.
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PMID:In vivo selection of respiratory syncytial viruses resistant to palivizumab. 1576 98

Intranasal infection of BALB/c mice with respiratory syncytial virus (RSV)-A2 (0.5 x 10(8) - 2.0 x 10(8) plaque-forming units, PFU) produced disease characterized by weight loss (2-3 g) and mortality (60%-100%) with the mean day of death ranging from 6-7 d after infection. The extent of RSV disease was inoculum titer-dependent and required a replication competent virus. Lung titers of virus peaked at 0.5-1 x 10(6) PFU/g wet weight. Bronchoalveolar lavage fluid (BALF) levels of IL-1beta, TNF-alpha, INF-gamma IL-12, IL-6, MIP-1alpha, RANTES, and protein were elevated, whereas IL-2, IL-4, IL-5, IL-13, and IL-10 were unchanged. Histological assessment of lungs revealed marked inflammatory pathology characterized by bronchiolitis, vasculitis, and interstitial pneumonia. Whole-body plethysmography revealed significant disease-associated deficits of respiratory function. Therapy with ribavirin administered either by the intranasal, subcutaneous, or oral route significantly reduced disease in a dose-dependent manner. Delaying the initiation of therapy resulted in a loss of activity for ribavirin. Synagis administered either intramuscularly as a single dose in prophylaxis or intranasally in prophylaxis, followed by therapy, also significantly reduced disease in a dose-dependent manner. Infection of mice with a high titer inoculum of RSV-A2 resulted in severe and fatal pulmonary disease that was responsive to treatment. This model may be useful to characterize the in vivo activity of experimental therapies for RSV infection.
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PMID:Primary infection of mice with high titer inoculum respiratory syncytial virus: characterization and response to antiviral therapy. 1579 Dec 94

We describe here the selection of ultra-potent anti-respiratory syncytial virus (RSV) antibodies for preventing RSV infection. A large number of antibody variants derived from Synagis (palivizumab), an anti-RSV monoclonal antibody that targets RSV F protein, were generated by a directed evolution approach that allowed convenient manipulation of the binding kinetics. Palivizumab variants with about 100-fold slower dissociation rates or with fivefold faster association rates were identified and tested for their ability to neutralize virus in a microneutralization assay. Our data reveal a major differential effect of the association and dissociation rates on the RSV neutralization, particularly for intact antibodies wherein the association rate plays the predominant role. Furthermore, we found that antibody binding valence also plays a critical role in mediating the viral neutralization through a mechanism that is likely unrelated to antibody size or binding avidity. We applied an iterative mutagenesis approach, and thereafter were able to identify palivizumab Fab variants with up to 1500-fold improvement and palivizumab IgG variants with up to 44-fold improvement in the ability to neutralize RSV. These anti-RSV antibodies likely will offer great clinical potential for RSV immunoprophylaxis. In addition, our findings provide insights into engineering potent antibody therapeutics for other disease targets.
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PMID:Ultra-potent antibodies against respiratory syncytial virus: effects of binding kinetics and binding valence on viral neutralization. 1590 31

Schefflera heptaphylla is a popular medicinal plant in southern China. Three caffeoylquinic acid derivatives, namely 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, and 3-O-caffeoylquinic acid, were isolated from this plant and investigated for their antiviral activity against respiratory syncytial virus (RSV). 3,4-Di-O-caffeoylquinic acid and 3,5-di-O-caffeoylquinic acid possessed potent anti-RSV activity. The median inhibitory concentrations (IC50) of 3,4-di-O-caffeoylquinic acid and 3,5-di-O-caffeoylquinic acid against RSV were 2.33 microM (1.2 microg/ml) and 1.16 microM (0.6 microg/ml), respectively, in a plaque reduction assay. The dicaffeoylquinic acids exhibited minimal cytotoxicity against HEp-2 cells with median cytotoxic concentration (CC50) higher than 1000 microM. The maximal non-cytotoxic concentration (MNCC) of the two dicaffeoylquinic acids were about 96.7 microM, which suggested their anti-RSV effect was not due to cytotoxicity. The antiviral action of 3,4-di-O-caffeoylquinic acid and 3,5-di-O-caffeoylquinic acid was specific against RSV, as they had no obvious antiviral activity against influenza A (Flu A), Coxsackie B3 (Cox B3), and Herpes simplex type one (HSV-1) viruses. Studies were performed that indicated that the dicaffeoylquinic acids could inhibit RSV directly, extracellularly, but only at much higher concentrations than seen in standard assays. Moreover, they could not inhibit RSV attachment to host cells, and could not protect HEp-2 cells from RSV infection at lower concentrations. The data suggest that the compounds exerted their anti-RSV effects via the inhibition of virus-cell fusion in the early stage, and the inhibition of cell-cell fusion at the end of the RSV replication cycle.
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PMID:Antiviral activity and mode of action of caffeoylquinic acids from Schefflera heptaphylla (L.) Frodin. 1614 Apr

Respiratory syncytial virus (RSV) is a major cause of respiratory illness in infants, immunocompromised patients, and the elderly. New antiviral agents would be important tools in the treatment of acute RSV disease. RSV encodes its own RNA-dependent RNA polymerase that is responsible for the synthesis of both genomic RNA and subgenomic mRNAs. The viral polymerase also cotranscriptionally caps and polyadenylates the RSV mRNAs at their 5' and 3' ends, respectively. We have previously reported the discovery of the first nonnucleoside transcriptase inhibitor of RSV polymerase through high-throughput screening. Here we report the design of inhibitors that have improved potency both in vitro and in antiviral assays and that also exhibit activity in a mouse model of RSV infection. We have isolated virus with reduced susceptibility to this class of inhibitors. The mutations conferring resistance mapped to a novel motif within the RSV L gene, which encodes the catalytic subunit of RSV polymerase. This motif is distinct from the catalytic region of the L protein and bears some similarity to the nucleotide binding domain within nucleoside diphosphate kinases. These findings lead to the hypothesis that this class of inhibitors may block synthesis of RSV mRNAs by inhibiting guanylylation of viral transcripts. We show that short transcripts produced in the presence of inhibitor in vitro do not contain a 5' cap but, instead, are triphosphorylated, confirming this hypothesis. These inhibitors constitute useful tools for elucidating the molecular mechanism of RSV capping and represent valid leads for the development of novel anti-RSV therapeutics.
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PMID:Inhibitors of respiratory syncytial virus replication target cotranscriptional mRNA guanylylation by viral RNA-dependent RNA polymerase. 1618 12

Respiratory syncytial virus infection continues to be one of the most important health problems in infancy. Active prophylaxis against this infection (i.e., vaccination) is not available. Therefore, protection of high-risk infants is possible only by passive prophylaxis with specific antibodies. Palivizumab (Synagis) and respiratory syncytial virus intravenous immune globulin are licensed by the US Food and Drug Administration for the prevention of severe lower respiratory tract infections caused by respiratory syncytial virus in infants with bronchopulmonary dysplasia, infants with a history of premature birth (< or =35 weeks gestational age) and children with hemodynamically significant congenital heart disease. Palivizumab is a humanized monoclonal antibody produced by recombinant DNA technology, directed to an epitope in the A antigenic side of the F-protein of the respiratory syncytial virus. This review discusses the characteristics of this drug in detail.
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PMID:Palivizumab in the prophylaxis of respiratory syncytial virus infection. 1620 63

Palivizumab is a monocloncal antibody used for prevention of respiratory syncytial virus infection. This study reviews the literature regarding evidence of efficacy, safety and cost-effectiveness. The only randomised controlled trial into efficacy of palivizumab in preterm infants demonstrates clinical benefit and suggests a favourable safety profile. Further studies, however, do not provide evidence that costs saved by the reduction in hospitalisation would outweigh actual costs of the immunization for the recommended indications. There is considerable controversy over which groups of patients to include in immunization programs and analyses of cost-effectiveness are complicated by the fact that incidence of RSV infection, rates of hospitalisation and ventilation, health care costs and economic resources are variable among different health care systems and settings. Studies of cost-analysis, despite their implicit weaknesses, do not currently support the widespread use of palivizumab. In the absence of high quality cost-benefit analysis, we currently only recommend the use of palivizumab in infants at high risk of severe bronchiolitis, such as those with active chronic lung disease of prematurity. To illustrate current practice we also present data from an audit of the use of palivizumab in a regional centre in the North-East of England.
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PMID:Passive immunisation of preterm infants with palivizumab against RSV infection. 1623 60


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