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RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2

SARS-CoV-2, the virus behind the deadly COVID-19 pandemic, continues to spread globally even as vaccine strategies are proving effective in preventing hospitalizations and deaths. However, evolving variants of the virus appear to be more transmissive and vaccine efficacy toward them is waning. As a...

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Autores principales: Vesuna, Farhad, Akhrymuk, Ivan, Smith, Amy, Winnard, Paul T., Lin, Shih-Chao, Panny, Lauren, Scharpf, Robert, Kehn-Hall, Kylene, Raman, Venu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9453862/
https://www.ncbi.nlm.nih.gov/pubmed/36090095
http://dx.doi.org/10.3389/fmicb.2022.959577
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author Vesuna, Farhad
Akhrymuk, Ivan
Smith, Amy
Winnard, Paul T.
Lin, Shih-Chao
Panny, Lauren
Scharpf, Robert
Kehn-Hall, Kylene
Raman, Venu
author_facet Vesuna, Farhad
Akhrymuk, Ivan
Smith, Amy
Winnard, Paul T.
Lin, Shih-Chao
Panny, Lauren
Scharpf, Robert
Kehn-Hall, Kylene
Raman, Venu
author_sort Vesuna, Farhad
collection PubMed
description SARS-CoV-2, the virus behind the deadly COVID-19 pandemic, continues to spread globally even as vaccine strategies are proving effective in preventing hospitalizations and deaths. However, evolving variants of the virus appear to be more transmissive and vaccine efficacy toward them is waning. As a result, SARS-CoV-2 will continue to have a deadly impact on public health into the foreseeable future. One strategy to bypass the continuing problem of newer variants is to target host proteins required for viral replication. We have used this host-targeted antiviral (HTA) strategy that targets DDX3X (DDX3), a host DEAD-box RNA helicase that is usurped by SARS-CoV-2 for virus production. We demonstrated that targeting DDX3 with RK-33, a small molecule inhibitor, reduced the viral load in four isolates of SARS-CoV-2 (Lineage A, and Lineage B Alpha, Beta, and Delta variants) by one to three log orders in Calu-3 cells. Furthermore, proteomics and RNA-seq analyses indicated that most SARS-CoV-2 genes were downregulated by RK-33 treatment. Also, we show that the use of RK-33 decreases TMPRSS2 expression, which may be due to DDX3s ability to unwind G-quadraplex structures present in the TMPRSS2 promoter. The data presented support the use of RK-33 as an HTA strategy to control SARS-CoV-2 infection, irrespective of its mutational status, in humans.
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spelling pubmed-94538622022-09-09 RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2 Vesuna, Farhad Akhrymuk, Ivan Smith, Amy Winnard, Paul T. Lin, Shih-Chao Panny, Lauren Scharpf, Robert Kehn-Hall, Kylene Raman, Venu Front Microbiol Microbiology SARS-CoV-2, the virus behind the deadly COVID-19 pandemic, continues to spread globally even as vaccine strategies are proving effective in preventing hospitalizations and deaths. However, evolving variants of the virus appear to be more transmissive and vaccine efficacy toward them is waning. As a result, SARS-CoV-2 will continue to have a deadly impact on public health into the foreseeable future. One strategy to bypass the continuing problem of newer variants is to target host proteins required for viral replication. We have used this host-targeted antiviral (HTA) strategy that targets DDX3X (DDX3), a host DEAD-box RNA helicase that is usurped by SARS-CoV-2 for virus production. We demonstrated that targeting DDX3 with RK-33, a small molecule inhibitor, reduced the viral load in four isolates of SARS-CoV-2 (Lineage A, and Lineage B Alpha, Beta, and Delta variants) by one to three log orders in Calu-3 cells. Furthermore, proteomics and RNA-seq analyses indicated that most SARS-CoV-2 genes were downregulated by RK-33 treatment. Also, we show that the use of RK-33 decreases TMPRSS2 expression, which may be due to DDX3s ability to unwind G-quadraplex structures present in the TMPRSS2 promoter. The data presented support the use of RK-33 as an HTA strategy to control SARS-CoV-2 infection, irrespective of its mutational status, in humans. Frontiers Media S.A. 2022-08-25 /pmc/articles/PMC9453862/ /pubmed/36090095 http://dx.doi.org/10.3389/fmicb.2022.959577 Text en Copyright © 2022 Vesuna, Akhrymuk, Smith, Winnard, Lin, Panny, Scharpf, Kehn-Hall and Raman. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Vesuna, Farhad
Akhrymuk, Ivan
Smith, Amy
Winnard, Paul T.
Lin, Shih-Chao
Panny, Lauren
Scharpf, Robert
Kehn-Hall, Kylene
Raman, Venu
RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2
title RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2
title_full RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2
title_fullStr RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2
title_full_unstemmed RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2
title_short RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2
title_sort rk-33, a small molecule inhibitor of host rna helicase ddx3, suppresses multiple variants of sars-cov-2
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9453862/
https://www.ncbi.nlm.nih.gov/pubmed/36090095
http://dx.doi.org/10.3389/fmicb.2022.959577
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