Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy
| Autor: | Christopher A. Alabi, Nir Ben-Tal, Alexander L. Greninger, Ksenia Rybkina, A. des Georges, Matteo Porotto, V. Más, A. Moscona, Tara C. Marcink, Francesca T. Bovier, Elon Yariv |
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| Přispěvatelé: | Marcink, T. C., Yariv, E., Rybkina, K., Mas, V., Bovier, F. T., des Georges, A., Greninger, A. L., Alabi, C. A., Porotto, M., Ben-Tal, N., Moscona, A., National Institute of Allergy and Infectious Diseases (United States) |
| Rok vydání: | 2020 |
| Předmět: |
Antiviral agent
viruses Cell Culture Techniques Sialic acid binding Viral protein structure Microbiology Antiviral Agents Virus Cell Line Cell membrane Small Molecule Libraries 03 medical and health sciences Viral entry Virology Viral receptor Drug Discovery medicine Humans Viral fusion protein Cryo-electron tomography 030304 developmental biology Host cell membrane 0303 health sciences HN Protein Paramyxoviridae Infections 030306 microbiology Chemistry Epithelial Cells Virus Internalization Therapeutics and Prevention Fusion protein Small molecule cryo-electron tomography QR1-502 3. Good health Cell biology High-Throughput Screening Assays Parainfluenza Virus 3 Human Molecular Docking Simulation viral fusion protein Antiviral agents medicine.anatomical_structure Viral Receptor viral protein structure Viral Fusion Proteins viral receptor Protein Binding Research Article |
| Zdroj: | mBio mBio, Vol 11, Iss 1, p e03203-19 (2020) Repisalud Instituto de Salud Carlos III (ISCIII) mBio, Vol 11, Iss 1 (2020) |
| ISSN: | 2150-7511 |
| Popis: | Paramyxoviruses, including human parainfluenza virus type 3, are internalized into host cells by fusion between viral and target cell membranes. The receptor binding protein, hemagglutinin-neuraminidase (HN), upon binding to its cell receptor, triggers conformational changes in the fusion protein (F). This action of HN activates F to reach its fusion-competent state. Using small molecules that interact with HN, we can induce the premature activation of F and inactivate the virus. To obtain highly active pretriggering compounds, we carried out a virtual modeling screen for molecules that interact with a sialic acid binding site on HN that we propose to be the site involved in activating F. We use cryo-electron tomography of authentic intact viral particles for the first time to directly assess the mechanism of action of this treatment on the conformation of the viral F protein and present the first direct observation of the induced conformational rearrangement in the viral F protein. The receptor binding protein of parainfluenza virus, hemagglutinin-neuraminidase (HN), is responsible for actively triggering the viral fusion protein (F) to undergo a conformational change leading to insertion into the target cell and fusion of the virus with the target cell membrane. For proper viral entry to occur, this process must occur when HN is engaged with host cell receptors at the cell surface. It is possible to interfere with this process through premature activation of the F protein, distant from the target cell receptor. Conformational changes in the F protein and adoption of the postfusion form of the protein prior to receptor engagement of HN at the host cell membrane inactivate the virus. We previously identified small molecules that interact with HN and induce it to activate F in an untimely fashion, validating a new antiviral strategy. To obtain highly active pretriggering candidate molecules we carried out a virtual modeling screen for molecules that interact with sialic acid binding site II on HN, which we propose to be the site responsible for activating F. To directly assess the mechanism of action of one such highly effective new premature activating compound, PAC-3066, we use cryo-electron tomography on authentic intact viral particles for the first time to examine the effects of PAC-3066 treatment on the conformation of the viral F protein. We present the first direct observation of the conformational rearrangement induced in the viral F protein. |
| Databáze: | OpenAIRE |
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