Investigation of the Host Kinome Response to Coronavirus Infection Reveals PI3K/mTOR Inhibitors as Betacoronavirus Antivirals

Host kinases play essential roles in the host cell cycle,
innate
immune signaling, the stress response to viral infection, and inflammation.
Previous work has demonstrated that coronaviruses specifically target
kinase cascades to subvert host cell responses to infection and rely
upon host kinase activity to phosphorylate viral proteins to enhance
replication. Given the number of kinase inhibitors that are already
FDA approved to treat cancers, fibrosis, and other human disease,
they represent an attractive class of compounds to repurpose for host-targeted
therapies against emerging coronavirus infections. To further understand
the host kinome response to betacoronavirus infection, we employed
multiplex inhibitory bead mass spectrometry (MIB-MS) following MERS-CoV
and SARS-CoV-2 infection of human lung epithelial cell lines. Our
MIB-MS analyses revealed activation of mTOR and MAPK signaling following
MERS-CoV and SARS-CoV-2 infection, respectively. SARS-CoV-2 host kinome
responses were further characterized using paired phosphoproteomics,
which identified activation of MAPK, PI3K, and mTOR signaling. Through
chemogenomic screening, we found that clinically relevant PI3K/mTOR
inhibitors were able to inhibit coronavirus replication at nanomolar
concentrations similar to direct-acting antivirals. This study lays
the groundwork for identifying broad-acting, host-targeted therapies
to reduce betacoronavirus replication that can be rapidly repurposed
during future outbreaks and epidemics. The proteomics, phosphoproteomics,
and MIB-MS datasets generated in this study are available in the Proteomics
Identification Database (PRIDE) repository under project identifiers
PXD040897 and PXD040901.