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

Simple item page
dc.contributor.authorVesuna, Farhaden
dc.contributor.authorAkhrymuk, Ivanen
dc.contributor.authorSmith, Amyen
dc.contributor.authorWinnard Jr, Paul T.en
dc.contributor.authorLin, Shih-Chaoen
dc.contributor.authorPanny, Laurenen
dc.contributor.authorScharpf, Roberten
dc.contributor.authorKehn-Hall, Kyleneen
dc.contributor.authorRaman, Venuen
dc.date.accessioned2022-10-14T13:41:19Zen
dc.date.available2022-10-14T13:41:19Zen
dc.date.issued2022-08-25en
dc.description.abstractSARS-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.en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fmicb.2022.959577en
dc.identifier.eissn1664-302Xen
dc.identifier.other959577en
dc.identifier.pmid36090095en
dc.identifier.urihttp://hdl.handle.net/10919/112164en
dc.identifier.volume13en
dc.language.isoenen
dc.publisherFrontiersen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectSARS-CoV-2en
dc.subjecthost-targeted antiviralen
dc.subjectRNA helicaseen
dc.subjectDDX3 inhibitoren
dc.subjectRK-33en
dc.subjectviral isolatesen
dc.subjectTMPRSS2en
dc.titleRK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2en
dc.title.serialFrontiers in Microbiologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
fmicb-13-959577.pdf
Size:
3.12 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download

Collections

Scholarly Works, Biomedical Sciences and Pathobiology
Scholarly Works, Center for Emerging, Zoonotic, and Arthropod-borne Pathogens (CeZAP)