Chemotherapy of respiratory syncytial virus infections: the final breakthrough

Clercq, Erik De

doi:10.1016/j.ijantimicag.2014.12.025

Cited by 25 publications

(18 citation statements)

References 27 publications

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“…Similar studies and reviews are needed in children, however, until these become available it seems reasonable to prescribe NAIs promptly (ideally within 2‐days of symptom onset) for children with bronchiectasis and proven influenza with either advanced disease or if they are hospitalized with a severe, acute exacerbation . Ongoing studies with small interfering RNA molecules and novel anti‐viral agents directed against RSV fusion‐proteins are being trialled in adults and so offer some hope for the future …”

Section: Treatments For Bronchiectasis (References In the Text)mentioning

confidence: 99%

Pediatric bronchiectasis: No longer an orphan disease

Goyal

Grimwood

Marchant

et al. 2016

Pediatric Pulmonology

137

140

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Bronchiectasis is described classically as a chronic pulmonary disorder characterized by a persistent productive cough and irreversible dilatation of one or more bronchi. However, in children unable to expectorate, cough may instead be wet and intermittent and bronchial dilatation reversible in the early stages. Although still considered an orphan disease, it is being recognized increasingly as causing significant morbidity and mortality in children and adults in both affluent and developing countries. While bronchiectasis has multiple etiologies, the final common pathway involves a complex interplay between the host, respiratory pathogens and environmental factors. These interactions lead to a vicious cycle of repeated infections, airway inflammation and tissue remodelling resulting in impaired airway clearance, destruction of structural elements within the bronchial wall causing them to become dilated and small airway obstruction. In this review, the current knowledge of the epidemiology, pathobiology, clinical features, and management of bronchiectasis in children are summarized. Recent evidence has emerged to improve our understanding of this heterogeneous disease including the role of viruses, and how antibiotics, novel drugs, antiviral agents, and vaccines might be used. Importantly, the management is no longer dependent upon extrapolating from the cystic fibrosis experience. Nevertheless, substantial information gaps remain in determining the underlying disease mechanisms that initiate and sustain the pathophysiological pathways leading to bronchiectasis. National and international collaborations, standardizing definitions of clinical and research end points, and exploring novel primary prevention strategies are needed if further progress is to be made in understanding, treating and even preventing this often life-limiting disease.

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Section: Treatments For Bronchiectasis (References In the Text)mentioning

confidence: 99%

Pediatric bronchiectasis: No longer an orphan disease

Goyal

Grimwood

Marchant

et al. 2016

Pediatric Pulmonology

137

140

View full text Add to dashboard Cite

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“…These compounds inhibited RSV replication at nanomolar concentrations, far surpassing the antiviral activity of ribavirin (EC 50 ¼ 5.8 mM, SI > 43). The latter is the only small molecule drug to treat RSV infections, but, as a consequence of its limited efficacy, the need of prolonged aerosol administration and the risk of toxicity, its use is limited to children at high risk [39]. Therefore, effective and safe drugs are strongly needed to treat severe RSV-linked respiratory pathologies which can also affect adults and, particularly, elderly.…”

Section: Inhibition Of Rsvmentioning

confidence: 99%

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Tonelli

Naesens

Gazzarrini

et al. 2017

European Journal of Medicinal Chemistry

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We have identified a series of 1-aryl-4,6-diamino-1,2-dihydrotriazines, structurally related to the antimalarial drug cycloguanil, as new inhibitors of influenza A and B virus and respiratory syncytial virus (RSV) via targeting of the host dihydrofolate reductase (DHFR) enzyme. Most analogues proved active against influenza B virus in the low micromolar range, and the best compounds (11, 13, 14 and 16) even reached the sub-micromolar potency of zanamivir (EC = 0.060 μM), and markedly exceeded (up to 327 times) the antiviral efficacy of ribavirin. Activity was also observed for two influenza A strains, including a virus with the S31N mutant form of M2 proton channel, which is the most prevalent resistance mutation for amantadine. Importantly, the compounds displayed nanomolar activity against RSV and a superior selectivity index, since the ratio of cytotoxic to antiviral concentration was >10,000 for the three most active compounds 11, 14 and 16 (EC ∼0.008 μM), far surpassing the potency and safety profile of the licensed drug ribavirin (EC = 5.8 μM, SI > 43).

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“…There is no vaccine against RSV, and monoclonal antibody prophylaxis is available only to a subset of infants considered to be at high risk for severe disease (Andabaka et al , 2013). Specific antivirals, including replication and fusion inhibitors, are currently in development (Gomez et al , 2014; De Clerq, 2015). Less attention has been directed towards therapeutic strategies designed to limit virus-induced inflammatory responses (Rosenberg & Domachowske, 2012).…”

Section: Introductionmentioning

confidence: 99%

Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection

et al. 2016

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Pattern recognition receptors (PRRs) engage microbial components in the lung, although their role in providing primary host defense against respiratory virus infection is not fully understood. We have previously shown that Gram-positive Lactobacillus plantarum (Lp) administered to the respiratory tract promotes full and sustained protection in response to an otherwise lethal mouse pneumovirus (PVM) infection, a robust example of heterologous immunity. While Lp engages PRRs TLR2 and NOD2 in ex vivo signaling assays, we found that Lp-mediated protection was unimpaired in single gene-deleted TLR2−/− and NOD2−/− mice. Here we demonstrate substantial loss of Lp-mediated protection in a double gene-deleted NOD2−/−TLR2−/− strain. Furthermore, we demonstrate protection against PVM infection by administration of the bi-functional NOD2-TLR2 agonist, CL-429. The bi-functional NOD2-TLR2 ligand CL-429 not only suppresses virus-induced inflammation, it is significantly more effective at preventing lethal infection than equivalent amounts of mono-molecular TLR2 and NOD2 agonists. Interestingly, and in contrast to biochemical NOD2 and/or TLR2 agonists, Lp remained capable of eliciting primary proinflammatory responses from NOD2−/−TLR2−/− mice in vivo and from alveolar macrophages challenged ex vivo. Taken together, we conclude that coordinate engagement of NOD2 and TLR2 constitutes a key step in the genesis of Lp-mediated protection from a lethal respiratory virus infection, and represents a critical target for modulation of virus-induced inflammatory pathology.

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Chemotherapy of respiratory syncytial virus infections: the final breakthrough

Cited by 25 publications

References 27 publications

Pediatric bronchiectasis: No longer an orphan disease

Pediatric bronchiectasis: No longer an orphan disease

Host dihydrofolate reductase (DHFR)-directed cycloguanil analogues endowed with activity against influenza virus and respiratory syncytial virus

Signaling via pattern recognition receptors NOD2 and TLR2 contributes to immunomodulatory control of lethal pneumovirus infection

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