ABSTRACT
Drug repurposing provides an opportunity to redeploy drugs, which ideally are already approved for use in humans, for the treatment of other diseases. For example, the repurposing of dexamethasone and baricitinib has played a crucial role in saving patient lives during the ongoing SARS-CoV-2 pandemic. There remains a need to expand therapeutic approaches to prevent life-threatening complications in patients with COVID-19. Using an in silico approach based on structural similarity to drugs already in clinical trials for COVID-19, potential drugs were predicted for repurposing. For a subset of identified drugs with different targets to their corresponding COVID-19 clinical trial drug, a mechanism of action analysis was applied to establish whether they might have a role in inhibiting the replication of SARS-CoV-2. Of sixty drugs predicted in this study, two with the potential to inhibit SARS-CoV-2 replication were identified using mechanism of action analysis. Triamcinolone is a corticosteroid that is structurally similar to dexamethasone; gallopamil is a calcium channel blocker that is structurally similar to verapamil. In silico approaches indicate possible mechanisms of action for both drugs in inhibiting SARS-CoV-2 replication. The identification of these drugs as potentially useful for patients with COVID-19 who are at a higher risk of developing severe disease supports the use of in silico approaches to facilitate quick and cost-effective drug repurposing. Such drugs could expand the number of treatments available to patients who are not protected by vaccination.
Subject(s)
COVID-19ABSTRACT
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.