scholarly journals A Druggable Pocket at the Nucleocapsid/Phosphoprotein Interaction Site of Human Respiratory Syncytial Virus

2015 ◽  
Vol 89 (21) ◽  
pp. 11129-11143 ◽  
Author(s):  
Mohamed Ouizougun-Oubari ◽  
Nelson Pereira ◽  
Bogdan Tarus ◽  
Marie Galloux ◽  
Safa Lassoued ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Inhibitory Activity ◽  
In Silico ◽  
Respiratory Infections ◽  
Structural Information ◽  
Pharmacophore Model ◽  
Ribonucleoprotein Complex ◽  
Syncytial Virus

ABSTRACTPresently, respiratory syncytial virus (RSV), the main cause of severe respiratory infections in infants, cannot be treated efficiently with antivirals. However, its RNA-dependent polymerase complex offers potential targets for RSV-specific drugs. This includes the recognition of its template, the ribonucleoprotein complex (RNP), consisting of genomic RNA encapsidated by the RSV nucleoprotein, N. This recognition proceeds via interaction between the phosphoprotein P, which is the main polymerase cofactor, and N. The determinant role of the C terminus of P, and more particularly of the last residue, F241, in RNP binding and viral RNA synthesis has been assessed previously. Here, we provide detailed structural insight into this crucial interaction for RSV polymerase activity. We solved the crystallographic structures of complexes between the N-terminal domain of N (N-NTD) and C-terminal peptides of P and characterized binding by biophysical approaches. Our results provide a rationale for the pivotal role of F241, which inserts into a well-defined N-NTD pocket. This primary binding site is completed by transient contacts with upstream P residues outside the pocket. Based on the structural information of the N-NTD:P complex, we identified inhibitors of this interaction, selected byin silicoscreening of small compounds, that efficiently bind to N and compete with Pin vitro. One of the compounds displayed inhibitory activity on RSV replication, thereby strengthening the relevance of N-NTD for structure-based design of RSV-specific antivirals.IMPORTANCERespiratory syncytial virus (RSV) is a widespread pathogen that is a leading cause of acute lower respiratory infections in infants worldwide. RSV cannot be treated efficiently with antivirals, and no vaccine is presently available, with the development of pediatric vaccines being particularly challenging. Therefore, there is a need for new therapeutic strategies that specifically target RSV. The interaction between the RSV phosphoprotein P and the ribonucleoprotein complex is critical for viral replication. In this study, we identified the main structural determinants of this interaction, and we used them to screen potential inhibitorsin silico. We found a family of molecules that were efficient competitors of Pin vitroand showed inhibitory activity on RSV replication in cellular assays. These compounds provide a basis for a pharmacophore model that must be improved but that holds promises for the design of new RSV-specific antivirals.

scholarly journals Respiratory Syncytial Virus Disease Severity in Young Children

2020 ◽  
Author(s):  
Zaid Haddadin ◽  
Stockton Beveridge ◽  
Kailee Fernandez ◽  
Danielle A Rankin ◽  
Varvara Probst ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Young Children ◽  
Disease Severity ◽  
Severity Score ◽  
Respiratory Infections ◽  
Virus Disease ◽  
Younger Age ◽  
Inpatient Settings ◽  
Syncytial Virus

Abstract Background Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infections (ARIs) in hospitalized children. Although prematurity and underlying medical conditions are known risk factors, most of these children are healthy, and factors including RSV load and subgroups may contribute to severity. Therefore, we aimed to evaluate the role of RSV in ARI severity and determine factors associated with increased RSV-ARI severity in young children. Methods Children aged <5 years with fever and/or ARI symptoms were recruited from the emergency department (ED) or inpatient settings at Vanderbilt Children’s Hospital. Nasal and/or throat swabs were tested using quantitative reverse-transcription polymerase chain reaction for common respiratory viruses, including RSV. A severity score was calculated for RSV-positive children. Results From November 2015 through July 2016, 898 participants were enrolled, and 681 (76%) had at least 1 virus detected, with 191 (28%) testing positive for RSV. RSV-positive children were more likely to be hospitalized, require intensive care unit admission, and receive oxygen compared with children positive for other viruses. Higher viral load, White race, younger age, and higher severity score were independently associated with hospitalization in RSV-positive children. No differences in disease severity were noted between RSV A and RSV B. Conclusions RSV was associated with increased ARI severity in young children enrolled from the ED and inpatient settings, but no differences in disease severity were noted between RSV A and RSV B. These findings emphasize the need for antiviral therapy and/or preventive measures such as vaccines against RSV in young children.

scholarly journals Mitoxantrone Shows In Vitro, but Not In Vivo Antiviral Activity against Human Respiratory Syncytial Virus

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1176
Author(s):  
Patricia G. de la Sota ◽  
Elena Lorente ◽  
Laura Notario ◽  
Carmen Mir ◽  
Oscar Zaragoza ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Infections ◽  
The Elderly ◽  
Human Respiratory Syncytial Virus ◽  
Mice Model ◽  
Drug Candidates ◽  
Antiviral Activities ◽  
Syncytial Virus

Human respiratory syncytial virus (HRSV) is the most common cause of severe respiratory infections in infants and young children, often leading to hospitalization. In addition, this virus poses a serious health risk in immunocompromised individuals and the elderly. HRSV is also a major nosocomial hazard in healthcare service units for patients of all ages. Therefore, the development of antiviral treatments against HRSV is a global health priority. In this study, mitoxantrone, a synthetic anthraquinone with previously reported in vitro antiprotozoal and antiviral activities, inhibits HRSV replication in vitro, but not in vivo in a mice model. These results have implications for preclinical studies of some drug candidates.

scholarly journals Role of G2-S16 Polyanionic Carbosilane Dendrimer in the Prevention of Respiratory Syncytial Virus Infection In Vitro and In Vivo in Mice

Polymers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 2141
Author(s):  
Ignacio Rodriguez-Izquierdo ◽  
Rafael Ceña-Diez ◽  
Maria Jesús Serramia ◽  
Rosa Rodriguez-Fernández ◽  
Isidoro Martínez ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Cell Surface ◽  
Host Cells ◽  
Carbosilane Dendrimer ◽  
Rsv Infection ◽  
Host Cell Surface ◽  
Syncytial Virus

The respiratory syncytial virus (RSV) causes respiratory infection and bronchiolitis, requiring hospitalization mainly in infants. The interaction between RSV, envelope glycoproteins G and F, and cell surface heparan sulfate proteoglycans (HSPG) is required for binding and entry into the host cells. A G2-S16 polyanionic carbosilane dendrimer was identified as a possible RSV inhibitor. We speculated that the G2-S16 dendrimer adheres to the host cell-surface HSPG, acts through binding to HS receptors, and prevents further RSV infection. The G2-S16 dendrimer was non-toxic when applied intranasally to Balb/c mice, and interestingly enough, this G2-S16 dendrimer inhibits 85% RSV. Therefore, our G2-S16 dendrimer could be a candidate for developing a new possible therapy against RSV infection.

scholarly journals Desenho e Validação de Primers In Silico para Detecção do Vírus Sincicial Respiratório Humano

REVISTA FIMCA ◽  
2017 ◽  
Vol 4 (1) ◽  
pp. 17-30
Author(s):  
Jackson Alves da Silva Queiroz ◽  
Luciane Soares Alves ◽  
Deusilene Souza Vieira Dall’acqua ◽  
Luan Felipo Botelho Souza
Keyword(s):  
Respiratory Syncytial Virus ◽  
In Silico ◽  
Human Respiratory Syncytial Virus ◽  
Base Pairs ◽  
Gene Encoding ◽  
Target Region ◽  
Glycoprotein G ◽  
Syncytial Virus ◽  
Delta G

Introdução: O desenvolvimento de primers é extremamente importante para pesquisas moleculares. Objetivos: O presente estudo objetivou desenhar e validar primers in silico para detecção do vírus sincicial respiratório humano (RSVH). Materiais e Métodos: Foi construído um banco de 100 sequências de genoma completo do Vírus Sincicial Respiratório Humano (RSVH) depositadas no Genbank (NCBI). Realizado um alinhamento múltiplo global utilizando o algoritimo Clustal W, mapeadas as regiões conservadas e selecionado os primers. Posteriormente submetidos a análise dos parâmetros especificidade, pela ferramenta BLAST, concentração de GC%, TMelting, comprimento, formação de dímeros e hairpin utilizando o software Oligo Analyser, validando-os para uso in vitro. Para discussão dos resultados, foram selecionados 14 primers de estudos realizados, submetidos à metodologia proposta neste estudo, comparando os dados obtidos. A região alvo escolhida foi o gene da Glicoproteína G, pela presença de sítios conservados. Resultados: Os primers amplificam um fragmento de 381pb, que submetido a uma segunda PCR, resulta em 109 pb correspondente ao tipo A do vírus e 168 pb para o tipo B, permitindo a detecção viral e a distinção de genótipos. Os primers possuem tamanho de 21 a 24 pb, com uma temperatura de melting entre 48,9 oC e 55,3 oC. A concentração de GC% varia de 33,3% a 52,4%. O número de bases complementares na análise de dímeros e hairpin manteve-se abaixo de 5 bases. A Energia Livre de Gibbs (Delta G) acima de -9 kcal.moles(-1) como desejado. Conclusão: Os valores obtidos na validação dos primers estão em concordância com os já utilizados em estudos de referência, validando assim o seu uso in vitro. Introduction: Developing primers is extremely important to molecular researches. Objectives: This study aims to drawing and validate in silico primers for detection of Human Respiratory Syncytial Virus (RSVH). Materials and Methods: It was built a database of 100 complete genome sequences of Human Respiratory Syncytial Virus (RSVH) deposited in the Genbank (NCBI), carried out a global multiple alignment using the algoritm Clustal W, thus mapping the conserved regions, and selecting primers, subsequently submitted to analysis of parameters such as specificity, by the BLAST tool, concentration of GC% TMelting, length, and formation of dimers and hairpins using the software Oligo Analyser, validating them to use in vitro. For discussion of the results, we selected 14 primers of studies already carried out and submitted the methodology proposed in this study, comparing the data obtained. The selected target region was the gene encoding the Glycoprotein G, by the presence of conserved sites. Results: The primers selected amplifies a fragment of 381 bp in the 1st PCR, which subjected to a second PCR results in 109 bp corresponding to the type A of the virus and 168 base pairs for the type Bwhat allows not only viral detection, as the distinction of the type to which it belongs. The primers have size from 21 to 24 base pairs, having a melting temperature (Tmelting) between 48,9o C and 55,3o C and GC% concentration ranging from 33.3% to 52.4%. The number of complementary bases in the dimers and hairpins analysis was maintained below 5 bases, while the Gibbs free energy (Delta G) was kept above kcal.mole -9(-1) as desired. Conclusion: All values obtained in the validation of the primers are in agreement with the ones already used in the reference studies, thereby validating its use in vitro.

scholarly journals Immunoprophylaxis of influenza, acute and recurrent respiratory infections during the COVID-19 pandemic

2021 ◽  
pp. 111-120
Author(s):  
A. A. Girina ◽  
A. L. Zaplatnikov ◽  
E. I. Burtseva ◽  
V. I. Svintsitskaya ◽  
I. D. Maykova ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Infections ◽  
Maximum Activity ◽  
Influenza Viruses ◽  
Bacterial Lysate ◽  
Good Tolerability ◽  
Recurrent Respiratory Infections ◽  
Syncytial Virus ◽  
Bacterial Lysates

The article notes features of the last epidemic season (2020-2021) in the form of extremely low activity of influenza viruses with SARS-CoV-2 remaining dominant in the etiological structure of acute respiratory viral infections. Presented own data indicating the heterogeneity of SARS-CoV-2 (Alpha, Delta, B.1.1.317, B.1.1.397, B.1.1.523) isolated from hospitalized patients was noted. An increase in the etiological role of bocavirus, alpha-coronavirus and metapneumovirus with a decrease in the frequency of parainfluenza viruses, adenoviruses, rhinoviruses and respiratory syncytial virus was established. An unusual shift of the period of maximum activity of respiratory syncytial virus to the 20th week was noted. Attention is paid to the need during the ongoing pandemic COVID-19 to fully immunize children as part of the National Immunization Calendar, also emphasized the role of mandatory annual vaccination against influenza. It is noted that the maximum protective effect of immunoprophylaxis of influenza acute and recurrent respiratory infections can be achieved with a combination of vaccination with bacterial lysates. The article presents a review of the literature and our data demonstrating the safety, good tolerability, and high clinical and immunological efficiency of polyvalent mechanical bacterial lysate for the prevention of acute and recurrent respiratory infections in children. It is shown that the use of polyvalent mechanical bacterial lysate during the prevaccination period makes it possible to substantially reduce the frequency of intercurrent infections, which reduces the number of temporary medical withdrawals and increases the coverage of vaccinations against influenza in organized groups to 85.1%. The role of trained immunity as one of the possible mechanisms providing nonspecific immunoprophylaxis during influenza vaccination and the use of bacterial lysates is discussed.

A study of respiratory infections in the elderly to assess the role of respiratory syncytial virus

1983 ◽  
Vol 7 (3) ◽  
pp. 236-247 ◽  
Author(s):  
F. Morales ◽  
M.A. Calder ◽  
J.M. Inglis ◽  
P.S. Murdoch ◽  
J. Williamson
Keyword(s):  
Respiratory Syncytial Virus ◽  
Respiratory Infections ◽  
The Elderly ◽  
Syncytial Virus
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