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A Druggable Pocket at the Nucleocapsid/Phosphoprotein Interaction Site of Human Respiratory Syncytial Virus
- Source :
- Journal of Virology, Journal of Virology, American Society for Microbiology, 2015, 89 (21), pp.11129-11143. ⟨10.1128/JVI.01612-15⟩, Journal of Virology, 2015, 89 (21), pp.11129-11143. ⟨10.1128/JVI.01612-15⟩
- Publication Year :
- 2015
- Publisher :
- American Society for Microbiology, 2015.
-
Abstract
- Presently, 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 by in silico screening of small compounds, that efficiently bind to N and compete with P in 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. IMPORTANCE Respiratory 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 inhibitors in silico . We found a family of molecules that were efficient competitors of P in vitro and 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.
- Subjects :
- Models, Molecular
MESH: Antiviral Agents
Magnetic Resonance Spectroscopy
Protein Conformation
Viral protein
MESH: Nucleocapsid
[SDV]Life Sciences [q-bio]
In silico
Immunology
Respiratory Syncytial Virus Infections
MESH: Respiratory Syncytial Virus, Human
Calorimetry
MESH: Drug Design
Biology
Crystallography, X-Ray
medicine.disease_cause
Antiviral Agents
MESH: Phosphoproteins
Microbiology
Virus
MESH: Respiratory Syncytial Virus Infections
MESH: Protein Conformation
X-Ray Diffraction
Virology
medicine
Humans
Binding site
Nucleocapsid
MESH: Calorimetry
Polymerase
MESH: Humans
MESH: Magnetic Resonance Spectroscopy
Structure and Assembly
MESH: X-Ray Diffraction
Phosphoproteins
MESH: Crystallography, X-Ray
3. Good health
Nucleoprotein
Luminescent Proteins
Viral replication
Drug Design
Respiratory Syncytial Virus, Human
Insect Science
Phosphoprotein
biology.protein
MESH: Luminescent Proteins
MESH: Models, Molecular
Subjects
Details
- ISSN :
- 10985514 and 0022538X
- Volume :
- 89
- Database :
- OpenAIRE
- Journal :
- Journal of Virology
- Accession number :
- edsair.doi.dedup.....86554ccaf6f4bd9b41293f3b104e8ce1