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

• DOI: 10.1021/acs.jproteome.3c00182
• Publication Date: 2023-08-27T12:00:51Z
• Authors: Ethan J. Fritch; Angie L. Mordant; Thomas S.K. Gilbert; Carrow I. Wells; Xuan Yang; Natalie K. Barker; Emily A. Madden; Kenneth H. Dinnon; Yixuan J. Hou; Longping V. Tse; Izabella N. Castillo; Amy C. Sims; Nathaniel J. Moorman; Premkumar Lakshma...; Timothy M. Willson; Laura E. Herring; Lee M. Graves; Ralph S. Baric
• Keywords: Kinome; Phosphoproteomics; Coronavirus

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