Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy

ABSTRACT 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...

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Autores principales:	T. C. Marcink, E. Yariv, K. Rybkina, V. Más, F. T. Bovier, A. des Georges, A. L. Greninger, C. A. Alabi, M. Porotto, N. Ben-Tal, A. Moscona
Formato:	article
Lenguaje:	EN
Publicado:	American Society for Microbiology 2020
Materias:	antiviral agents cryo-electron tomography viral fusion protein viral protein structure viral receptor Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/adba678942a648879d19aa2a2f186b02
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spelling	oai:doaj.org-article:adba678942a648879d19aa2a2f186b022021-11-15T15:56:58ZHijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy10.1128/mBio.03203-192150-7511https://doaj.org/article/adba678942a648879d19aa2a2f186b022020-02-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.03203-19https://doaj.org/toc/2150-7511ABSTRACT 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. IMPORTANCE 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.T. C. MarcinkE. YarivK. RybkinaV. MásF. T. BovierA. des GeorgesA. L. GreningerC. A. AlabiM. PorottoN. Ben-TalA. MosconaAmerican Society for Microbiologyarticleantiviral agentscryo-electron tomographyviral fusion proteinviral protein structureviral receptorMicrobiologyQR1-502ENmBio, Vol 11, Iss 1 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	antiviral agents cryo-electron tomography viral fusion protein viral protein structure viral receptor Microbiology QR1-502
spellingShingle	antiviral agents cryo-electron tomography viral fusion protein viral protein structure viral receptor Microbiology QR1-502 T. C. Marcink E. Yariv K. Rybkina V. Más F. T. Bovier A. des Georges A. L. Greninger C. A. Alabi M. Porotto N. Ben-Tal A. Moscona Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy
description	ABSTRACT 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. IMPORTANCE 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.
format	article
author	T. C. Marcink E. Yariv K. Rybkina V. Más F. T. Bovier A. des Georges A. L. Greninger C. A. Alabi M. Porotto N. Ben-Tal A. Moscona
author_facet	T. C. Marcink E. Yariv K. Rybkina V. Más F. T. Bovier A. des Georges A. L. Greninger C. A. Alabi M. Porotto N. Ben-Tal A. Moscona
author_sort	T. C. Marcink
title	Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy
title_short	Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy
title_full	Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy
title_fullStr	Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy
title_full_unstemmed	Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy
title_sort	hijacking the fusion complex of human parainfluenza virus as an antiviral strategy
publisher	American Society for Microbiology
publishDate	2020
url	https://doaj.org/article/adba678942a648879d19aa2a2f186b02
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Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy

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