Identification of RSV Fusion Protein Interaction Domains on the Virus Receptor, Nucleolin

Nucleolin is an essential cellular receptor to human respiratory syncytial virus (RSV). Pharmacological targeting of the nucleolin RNA binding domain RBD1,2 can inhibit RSV infections in vitro and in vivo; however, the site(s) on RBD1,2 which interact with RSV are not known. We undertook a series of...

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Bibliographic Details
Published in:	Viruses Vol. 13; no. 2; p. 261
Main Authors:	Mastrangelo, Peter, Chin, Allysia A, Tan, Stephanie, Jeon, Amy H, Ackerley, Cameron A, Siu, Karen K, Lee, Jeffrey E, Hegele, Richard G
Format:	Journal Article
Language:	English
Published:	Switzerland MDPI 08-02-2021 MDPI AG
Subjects:	Animals Antiviral Agents - pharmacology Cell Line Dogs fusion protein Humans Immunohistochemistry Madin Darby Canine Kidney Cells Microscopy, Electron Nucleolin Palivizumab - pharmacology Phosphoproteins - metabolism Protein Interaction Domains and Motifs - physiology protein–protein interactions Receptors, Virus - metabolism Respiratory Syncytial Viruses - metabolism RNA-Binding Proteins - metabolism RSV protein–protein interactions fusion protein RSV nucleolin
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Summary:	Nucleolin is an essential cellular receptor to human respiratory syncytial virus (RSV). Pharmacological targeting of the nucleolin RNA binding domain RBD1,2 can inhibit RSV infections in vitro and in vivo; however, the site(s) on RBD1,2 which interact with RSV are not known. We undertook a series of experiments designed to: document RSV-nucleolin co-localization on the surface of polarized MDCK cells using immunogold electron microscopy, to identify domains on nucleolin that physically interact with RSV using biochemical methods and determine their biological effects on RSV infection in vitro, and to carry out structural analysis toward informing future RSV drug development. Results of immunogold transmission and scanning electron microscopy showed RSV-nucleolin co-localization on the cell surface, as would be expected for a viral receptor. RSV, through its fusion protein (RSV-F), physically interacts with RBD1,2 and these interactions can be competitively inhibited by treatment with Palivizumab or recombinant RBD1,2. Treatment with synthetic peptides derived from two 12-mer domains of RBD1,2 inhibited RSV infection in vitro, with structural analysis suggesting these domains are potentially feasible for targeting in drug development. In conclusion, the identification and characterization of domains of nucleolin that interact with RSV provide the essential groundwork toward informing design of novel nucleolin-targeting compounds in RSV drug development.
Bibliography:	Current address: Department of Biology, Kwantlen Polytechnic University, Surrey, BC V3W 2M8, Canada.
ISSN:	1999-4915 1999-4915
DOI:	10.3390/v13020261