Significance The COVID-19 pandemic has highlighted the importance of prioritizing approved drugs to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. We experimentally screened 918 drugs, allowing us to evaluate the performance of the existing drug-repurposing methodologies, and used a consensus algorithm to increase the accuracy of the predictions. Finally, we screened in human cells the top-ranked drugs, identifying six drugs that reduced viral infection, four of which could be repurposed to treat COVID-19. The developed strategy has significance beyond COVID-19, allowing us to identify drug-repurposing candidates for neglected diseases. The COVID-19 pandemic has highlighted the need to quickly and reliably prioritize clinically approved compounds for their potential effectiveness for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Here, we deployed algorithms relying on artificial intelligence, network diffusion, and network proximity, tasking each of them to rank 6,340 drugs for their expected efficacy against SARS-CoV-2. To test the predictions, we used as ground truth 918 drugs experimentally screened in VeroE6 cells, as well as the list of drugs in clinical trials that capture the medical community’s assessment of drugs with potential COVID-19 efficacy. We find that no single predictive algorithm offers consistently reliable outcomes across all datasets and metrics. This outcome prompted us to develop a multimodal technology that fuses the predictions of all algorithms, finding that a consensus among the different predictive methods consistently exceeds the performance of the best individual pipelines. We screened in human cells the top-ranked drugs, obtaining a 62% success rate, in contrast to the 0.8% hit rate of nonguided screenings. Of the six drugs that reduced viral infection, four could be directly repurposed to treat COVID-19, proposing novel treatments for COVID-19. We also found that 76 of the 77 drugs that successfully reduced viral infection do not bind the proteins targeted by SARS-CoV-2, indicating that these network drugs rely on network-based mechanisms that cannot be identified using docking-based strategies. These advances offer a methodological pathway to identify repurposable drugs for future pathogens and neglected diseases underserved by the costs and extended timeline of de novo drug development.
【저자키워드】 Drug repurposing, Infectious diseases, Systems biology, network medicine, 【초록키워드】 COVID-19, SARS-CoV-2, viral infection, Efficacy, coronavirus, clinical trial, Diseases, COVID-19 pandemic, artificial intelligence, drugs, clinical trials, drug, outcome, severe acute respiratory syndrome Coronavirus, approved drugs, Protein, infections, Viral, pathogen, Accuracy, Algorithm, Effectiveness, pathway, Pathogens, dataset, respiratory, disease, mechanism, capture, best, Predictive, can not, approved drug, Metrics, Consensus, acute respiratory syndrome, Algorithms, acute respiratory syndrome coronavirus, acute respiratory syndrome coronavirus 2, Compound, human cells, candidate, treat, VeroE6 cells, de novo, diffusion, offer, human cell, screenings, identify, develop, evaluate, clinically, approved, reduced, screened, expected, methodological, Significance, treatments for COVID-19, 【제목키워드】 COVID-19, network,