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RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X

Viral disease is one of the greatest burdens for human health worldwide, with an urgent need for efficacious antiviral strategies. While antiviral drugs are available, in many cases, they are prone to the development of drug resistance. A way to overcome drug resistance associated with common antivi...

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Autores principales: Yang, Sundy N. Y., Atkinson, Sarah C., Audsley, Michelle D., Heaton, Steven M., Jans, David A., Borg, Natalie A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016805/
https://www.ncbi.nlm.nih.gov/pubmed/31936642
http://dx.doi.org/10.3390/cells9010170
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author Yang, Sundy N. Y.
Atkinson, Sarah C.
Audsley, Michelle D.
Heaton, Steven M.
Jans, David A.
Borg, Natalie A.
author_facet Yang, Sundy N. Y.
Atkinson, Sarah C.
Audsley, Michelle D.
Heaton, Steven M.
Jans, David A.
Borg, Natalie A.
author_sort Yang, Sundy N. Y.
collection PubMed
description Viral disease is one of the greatest burdens for human health worldwide, with an urgent need for efficacious antiviral strategies. While antiviral drugs are available, in many cases, they are prone to the development of drug resistance. A way to overcome drug resistance associated with common antiviral therapies is to develop antivirals targeting host cellular co-factors critical to viral replication, such as DEAD-box helicase 3 X-linked (DDX3X), which plays key roles in RNA metabolism and the antiviral response. Here, we use biochemical/biophysical approaches and infectious assays to show for the first time that the small molecule RK-33 has broad-spectrum antiviral action by inhibiting the enzymatic activities of DDX3X. Importantly, we show that RK-33 is efficacious at low micromolar concentrations in limiting infection by human parainfluenza virus type 3 (hPIV-3), respiratory syncytial virus (RSV), dengue virus (DENV), Zika virus (ZIKV) or West Nile virus (WNV)—for all of which, no Food and Drug Administration (FDA)-approved therapeutic is widely available. These findings establish for the first time that RK-33 is a broad-spectrum antiviral agent that blocks DDX3X’s catalytic activities in vitro and limits viral replication in cells.
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spelling pubmed-70168052020-02-28 RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X Yang, Sundy N. Y. Atkinson, Sarah C. Audsley, Michelle D. Heaton, Steven M. Jans, David A. Borg, Natalie A. Cells Article Viral disease is one of the greatest burdens for human health worldwide, with an urgent need for efficacious antiviral strategies. While antiviral drugs are available, in many cases, they are prone to the development of drug resistance. A way to overcome drug resistance associated with common antiviral therapies is to develop antivirals targeting host cellular co-factors critical to viral replication, such as DEAD-box helicase 3 X-linked (DDX3X), which plays key roles in RNA metabolism and the antiviral response. Here, we use biochemical/biophysical approaches and infectious assays to show for the first time that the small molecule RK-33 has broad-spectrum antiviral action by inhibiting the enzymatic activities of DDX3X. Importantly, we show that RK-33 is efficacious at low micromolar concentrations in limiting infection by human parainfluenza virus type 3 (hPIV-3), respiratory syncytial virus (RSV), dengue virus (DENV), Zika virus (ZIKV) or West Nile virus (WNV)—for all of which, no Food and Drug Administration (FDA)-approved therapeutic is widely available. These findings establish for the first time that RK-33 is a broad-spectrum antiviral agent that blocks DDX3X’s catalytic activities in vitro and limits viral replication in cells. MDPI 2020-01-09 /pmc/articles/PMC7016805/ /pubmed/31936642 http://dx.doi.org/10.3390/cells9010170 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Yang, Sundy N. Y.
Atkinson, Sarah C.
Audsley, Michelle D.
Heaton, Steven M.
Jans, David A.
Borg, Natalie A.
RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X
title RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X
title_full RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X
title_fullStr RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X
title_full_unstemmed RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X
title_short RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X
title_sort rk-33 is a broad-spectrum antiviral agent that targets dead-box rna helicase ddx3x
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016805/
https://www.ncbi.nlm.nih.gov/pubmed/31936642
http://dx.doi.org/10.3390/cells9010170
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