RK-33, a small molecule inhibitor of host RNA helicase DDX3, suppresses multiple variants of SARS-CoV-2
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (ScreenIT)
Abstract
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.
Article activity feed
-
-
SciScore for 10.1101/2022.02.28.482334: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources After QC, the filtered clean reads were aligned to the reference human genome (hg38) using HISAT2 and the statistics of the mapping rate and the distribution of reads on the reference sequence were used to determine whether the alignment result passes the second QC of alignment using FastQC. HISAT2suggested: (HISAT2, RRID:SCR_015530)FastQCsuggested: (FastQC, RRID:SCR_014583)This was followed by gene quantification analysis and other analysis based on gene expression such as PCA, correlations, and differential … SciScore for 10.1101/2022.02.28.482334: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics not detected. Sex as a biological variable not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Table 2: Resources
Software and Algorithms Sentences Resources After QC, the filtered clean reads were aligned to the reference human genome (hg38) using HISAT2 and the statistics of the mapping rate and the distribution of reads on the reference sequence were used to determine whether the alignment result passes the second QC of alignment using FastQC. HISAT2suggested: (HISAT2, RRID:SCR_015530)FastQCsuggested: (FastQC, RRID:SCR_014583)This was followed by gene quantification analysis and other analysis based on gene expression such as PCA, correlations, and differential gene screening using DeSEQ2. DeSEQ2suggested: (DESeq2, RRID:SCR_015687)We also performed significant enrichment analysis of GO function on differentially expressed genes and significance enrichment analysis of pathways analysis using REACTOME REACTOMEsuggested: (Reactome, RRID:SCR_003485)Fragmentation spectra were processed by Proteome Discoverer v2.4 (PD2.4, ThermoFisher Scientific) and searched with Mascot v. Proteome Discoverersuggested: (Proteome Discoverer, RRID:SCR_014477)Peptide identifications from the Mascot searches were processed within PD2.4 using Percolator at a 5% False Discovery Rate confidence threshold, based on an auto-concatenated decoy database search Percolatorsuggested: (OMSSAPercolator, RRID:SCR_000287)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
-
