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Title: A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid

Abstract

Polyamides have been shown to bind double-stranded DNA by complementing the curvature of the minor groove and forming various hydrogen bonds with DNA. Several polyamide molecules have been found to have potent antiviral activities against papillomavirus, a double-stranded DNA virus. By analogy, we reason that polyamides may also interact with the structured RNA bound in the nucleocapsid of a negative-strand RNA virus. For this work, Vesicular stomatitis virus (VSV) was selected as a prototype virus to test this possibility since its genomic RNA encapsidated in the nucleocapsid forms a structure resembling one strand of an A-form RNA duplex. One polyamide molecule, UMSL1011, was found to inhibit infection of VSV. To confirm that the polyamide targeted the nucleocapsid, a nucleocapsid-like particle (NLP) was incubated with UMSL1011. The encapsidated RNA in the polyamide-treated NLP was protected from thermo-release and digestion by RNase A. UMSL1011 also inhibits viral RNA synthesis in the intracellular activity assay for the viral RNA-dependent RNA polymerase. The crystal structure revealed that UMSL1011 binds the structured RNA in the nucleocapsid. The conclusion of our studies is that the RNA in the nucleocapsid is a viable antiviral target of polyamides. Since the RNA structure in the nucleocapsid is similar inmore » all negative-strand RNA viruses, polyamides may be optimized to target the specific RNA genome of a negative-strand RNA virus, such as respiratory syncytial virus and Ebola virus.« less

Authors:
 [1];  [1];  [2];  [2];  [2];  [1]
  1. Georgia State Univ., Atlanta, GA (United States)
  2. Univ. of Missouri, St. Louis, MO (United States)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
National Institutes of Health (NIH); University of Missouri Research Board; National Science Foundation (NSF)
OSTI Identifier:
1433705
Grant/Contract Number:  
R01 AI106307; 0959360; NSF DBI 0922879
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 92; Journal Issue: 8; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; RNA structure; antiviral agents; negative-strand RNA virus; nucleocapsid; viral RNA synthesis

Citation Formats

Gumpper, Ryan H., Li, Weike, Castañeda, Carlos H., Scuderi, M. José, Bashkin, James K., and Luo, Ming. A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid. United States: N. p., 2018. Web. doi:10.1128/JVI.00146-18.
Gumpper, Ryan H., Li, Weike, Castañeda, Carlos H., Scuderi, M. José, Bashkin, James K., & Luo, Ming. A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid. United States. doi:10.1128/JVI.00146-18.
Gumpper, Ryan H., Li, Weike, Castañeda, Carlos H., Scuderi, M. José, Bashkin, James K., and Luo, Ming. Wed . "A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid". United States. doi:10.1128/JVI.00146-18. https://www.osti.gov/servlets/purl/1433705.
@article{osti_1433705,
title = {A Polyamide Inhibits Replication of Vesicular Stomatitis Virus by Targeting RNA in the Nucleocapsid},
author = {Gumpper, Ryan H. and Li, Weike and Castañeda, Carlos H. and Scuderi, M. José and Bashkin, James K. and Luo, Ming},
abstractNote = {Polyamides have been shown to bind double-stranded DNA by complementing the curvature of the minor groove and forming various hydrogen bonds with DNA. Several polyamide molecules have been found to have potent antiviral activities against papillomavirus, a double-stranded DNA virus. By analogy, we reason that polyamides may also interact with the structured RNA bound in the nucleocapsid of a negative-strand RNA virus. For this work, Vesicular stomatitis virus (VSV) was selected as a prototype virus to test this possibility since its genomic RNA encapsidated in the nucleocapsid forms a structure resembling one strand of an A-form RNA duplex. One polyamide molecule, UMSL1011, was found to inhibit infection of VSV. To confirm that the polyamide targeted the nucleocapsid, a nucleocapsid-like particle (NLP) was incubated with UMSL1011. The encapsidated RNA in the polyamide-treated NLP was protected from thermo-release and digestion by RNase A. UMSL1011 also inhibits viral RNA synthesis in the intracellular activity assay for the viral RNA-dependent RNA polymerase. The crystal structure revealed that UMSL1011 binds the structured RNA in the nucleocapsid. The conclusion of our studies is that the RNA in the nucleocapsid is a viable antiviral target of polyamides. Since the RNA structure in the nucleocapsid is similar in all negative-strand RNA viruses, polyamides may be optimized to target the specific RNA genome of a negative-strand RNA virus, such as respiratory syncytial virus and Ebola virus.},
doi = {10.1128/JVI.00146-18},
journal = {Journal of Virology},
issn = {0022-538X},
number = 8,
volume = 92,
place = {United States},
year = {2018},
month = {2}
}

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