Targeting SARS-CoV-2 Main Protease (MPro) with Kinase Inhibitors: A Promising Approach for Discovering Antiviral and Anti-inflammatory Molecules against SARS-CoV-2

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)virus infected over 688 million people worldwide, causing public healthconcern and approximately 6.8 million deaths due to COVID-19. COVID-19,especially severe cases, is characterized by exacerbated lung inflammationwith an increase of pro-inflammatory cytokines. In addition to antiviraldrugs, there is a need for anti-inflammatory therapies to treat allphases of COVID-19. One of the most attractive drug targets for COVID-19is the SARS-CoV-2 main protease (MPro), an enzyme responsible forcleaving polyproteins formed after the translation of viral RNA, whichis essential for viral replication. MPro inhibitors, therefore, havethe potential to stop viral replication and act as antiviral drugs.Considering that several kinase inhibitors are known for their actionin inflammatory pathways, this could also be investigated toward apotential anti-inflammatory treatment for COVID-19. Therefore, theuse of kinase inhibitors against SARS-CoV-2 MPro may be a promisingstrategy to find molecules with dual activity antiviral andanti-inflammatory. Considering this, the potential of six kinase inhibitorsagainst SARS-CoV-2 MPro were evaluated in silico and in vitro, includingBaricitinib, Tofacitinib, Ruxolitinib, BIRB-796, Skepinone-L, andSorafenib. To assess the inhibitory potential of the kinase inhibitors,a continuous fluorescent-based enzyme activity assay was optimizedwith SARS-CoV-2 MPro and MCA-AVLQSGFR-K(Dnp)-K-NH2 (substrate). BIRB-796and Baricitinib were identified as inhibitors of SARS-CoV-2 MPro,presenting IC50 values of 7.99 and 25.31 & mu;M, respectively.As they are also known for their anti-inflammatory action, both areprototype compounds with the potential to present antiviral and anti-inflammatoryactivity against SARS-CoV-2 infection.