Hijacking the Fusion Complex of Human Parainfluenza Virus as an Antiviral Strategy.
Antiviral Agents
/ isolation & purification
Cell Culture Techniques
Cell Line
Drug Discovery
Epithelial Cells
/ drug effects
HN Protein
/ genetics
High-Throughput Screening Assays
Humans
Molecular Docking Simulation
Parainfluenza Virus 3, Human
/ drug effects
Paramyxoviridae Infections
/ drug therapy
Protein Binding
/ drug effects
Small Molecule Libraries
/ pharmacology
Viral Fusion Proteins
/ antagonists & inhibitors
Virus Internalization
/ drug effects
antiviral agents
cryo-electron tomography
viral fusion protein
viral protein structure
viral receptor
Journal
mBio
ISSN: 2150-7511
Titre abrégé: mBio
Pays: United States
ID NLM: 101519231
Informations de publication
Date de publication:
11 02 2020
11 02 2020
Historique:
entrez:
13
2
2020
pubmed:
13
2
2020
medline:
21
10
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32047132
pii: mBio.03203-19
doi: 10.1128/mBio.03203-19
pmc: PMC7018645
pii:
doi:
Substances chimiques
Antiviral Agents
0
HN Protein
0
Small Molecule Libraries
0
Viral Fusion Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAID NIH HHS
ID : R01 AI031971
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI114736
Pays : United States
Informations de copyright
Copyright © 2020 Marcink et al.
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