Identification of SARS-CoV-2 induced pathways reveal drug repurposing strategies

Han, Namshik; Hwang, Woochang; Tzelepis, Konstantinos; Schmerer, Patrick; Yankova, Eliza; MacMahon, Méabh; Lei, Winnie; Katritsis, Nicholas M; Liu, Anika; Schuldt, Alison; Harris, Rebecca; Chapman, Kathryn; McCaughan, Frank; Weber, Friedemann; Kouzarides, Tony

The global outbreak of SARS-CoV-2 necessitates the rapid development of new therapies against COVID-19 infection. Here, we present the identification of 200 approved drugs, appropriate for repurposing against COVID-19. We constructed a SARS-CoV-2-induced protein (SIP) network, based on disease signatures defined by COVID-19 multi-omic datasets(Bojkova et al., 2020; Gordon et al., 2020), and cross-examined these pathways against approved drugs. This analysis identified 200 drugs predicted to target SARS-CoV-2-induced pathways, 40 of which are already in COVID-19 clinical trials(Clinicaltrials.gov, 2020) testifying to the validity of the approach. Using artificial neural network analysis we classified these 200 drugs into 9 distinct pathways, within two overarching mechanisms of action (MoAs): viral replication (130) and immune response (70). A subset of drugs implicated in viral replication were tested in cellular assays and two (proguanil and sulfasalazine) were shown to inhibit replication. This unbiased and validated analysis opens new avenues for the rapid repurposing of approved drugs into clinical trials.