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

Abstract

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.

Therapeutic Targeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19

“…Aside from having well-known anti-inflammatory properties, some of the drugs tested also have reported antiviral properties against SARS-CoV-2. Dimethyl fumarate, mometasone, calcitriol, and sulfasalazine, potently inhibited SARS-CoV-2 replication in vitro in Vero E6 cells (Han et al, 2020;Matsuyama et al, 2020;Mok et al, 2020;Olagnier et al, 2020). The antiviral activities of Glycyrrhizin have been extensively studied in the context of other human viruses and most notably, the drug was found to potently suppress replication of two clinical isolates of SARSassociated coronavirus in Vero cells (Cinatl et al, 2003), and preliminarily, neutralize SARS-CoV-2 by inhibiting the viral main protease (van de Sand et al, 2021).…”

A system biology approach identifies candidate drugs to reduce mortality in severely ill COVID-19 patients

“…Similarly to Zotatifin, the rocaglate CR-1-31-B was shown to potently inhibit SARS-CoV-2 replication at low nanomolar doses in vitro and ex vivo ( 60 ). Both Tacrolimus and Zotatifin were among drugs identified by in vitro and in silico models as candidate drugs to treat COVID-19 ( 16, 17, 56 ). Nintedanib is a drug used to treat pulmonary fibrosis.…”

In vitroTargeting of Transcription Factors to Control the Cytokine Release Syndrome in COVID-19

“…Aside from having well-known anti-inflammatory properties, some of the drugs tested also have reported antiviral properties against SARS-CoV-2. Dimethyl fumarate, mometasone, calcitriol, and sulfasalazine, potently inhibited SARS-CoV-2 replication in vitro in Vero E6 cells (45)(46)(47)(48). The antiviral activities of Glycyrrhizin have been extensively studied in the context of other human viruses and most notably, the drug was found to potently suppress replication of two clinical isolates of SARS-associated coronavirus in Vero cells (49), and preliminarily, neutralize SARS-CoV-2 by inhibiting the viral main protease (50).…”