A new study based on computational analyses of how SARS-CoV-2 interacts with host cell proteins has identified 200 previously approved drugs that could be repurposed to treat COVID-19, 40 of which have already entered clinical trials. Furthermore, Namshik Han and colleagues identified 30 proteins induced by the SARS-CoV-2 virus that are targeted by 8 or more existing drugs, finding that nitric oxide production, which is important for viral synthesis, may be targeted by these drugs to fight infection. The researchers also identified 2 of these drugs with good safety profiles that successfully reduced viral replication in cellular assays, suggesting they could potentially prevent or treat COVID-19. Scientists now have sufficient data to understand the mechanisms by which SARS-CoV-2 interacts with host cell proteins better, illuminating possible individual targets and pathways. Existing approved drugs can be tested against these pathways to determine whether they may be repurposed to treat COVID-19. To advance this research, Han et al. developed a network of proteins induced by SARS-CoV-2 based on disease signatures and cross-examined these pathways against approved drugs. They used artificial neural network analysis to classify these 200 drugs into 9 distinct pathways within 2 overarching mechanisms: viral replication and immune response. Of the 1,573 proteins targeted by these 200 drugs, 66% were targeted by a single drug, while 0.19% (30 proteins) were targeted by 8 drugs or more. The researchers validated five drugs that targeted these 30 proteins using monkey cells in vitro, finding that proguanil (an anti-malarial drug) and sulfasalazine (a rheumatoid arthritis drug) showed antiviral effects without appearing to damage the cells. Further in vitro tests revealed that both drugs significantly reduced the phosphorylation of an important component of a protein kinase signaling pathway activated during SARS-CoV-2 infection, known to stimulate the release of cytokines that can cause potentially dangerous inflammation.