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

SARS-CoV-2, herpes behind the deadly COVID-19 pandemic, is constantly on the spread globally even while vaccine strategies are showing good at stopping hospitalizations and deaths. However, evolving variants from the virus seem to be more transmissive and vaccine effectiveness toward them is waning. Consequently, SARS-CoV-2 continuously possess a deadly effect on public health in to the near future. One technique to bypass the ongoing problem of newer variants would be to target host proteins needed for viral replication. We’ve used this host-targeted antiviral (HTA) strategy that targets DDX3X (DDX3), a number DEAD-box RNA helicase that’s usurped by SARS-CoV-2 for virus production. We shown that targeting DDX3 with RK-33, a little molecule inhibitor, reduced the viral load in four isolates of SARS-CoV-2 (Lineage A, and Lineage B Alpha, Beta, and Delta variants) by 1 to 3 log orders in Calu-3 cells. In addition, proteomics and RNA-seq analyses established that most SARS-CoV-2 genes were downregulated by RK-33 treatment. Also, we reveal that using RK-33 decreases TMPRSS2 expression, which can be because of RK-33 DDX3s capability to unwind G-quadraplex structures contained in the TMPRSS2 promoter. The information presented support using RK-33 being an HTA technique to control SARS-CoV-2 infection, regardless of its mutational status, in humans.