Integrated Data Analysis Uncovers New COVID-19 Related Genes and Potential Drug Re-Purposing Candidates.

The COVID-19 pandemic is an acute and rapidly evolving global health crisis. To better understand this disease's molecular basis and design therapeutic strategies, we built upon the recently proposed concept of an integrated cell, iCell, fusing three omics, tissue-specific human molecular interaction networks. We applied this methodology to construct infected and control iCells using gene expression data from patient samples and three cell lines. We found large differences between patient-based and cell line-based iCells (both infected and control), suggesting that cell lines are ill-suited to studying this disease. We compared patient-based infected and control iCells and uncovered genes whose functioning (wiring patterns in iCells) is altered by the disease. We validated in the literature that 18 out of the top 20 of the most rewired genes are indeed COVID-19-related. Since only three of these genes are targets of approved drugs, we applied another data fusion step to predict drugs for re-purposing. We confirmed with molecular docking that the predicted drugs can bind to their predicted targets. Our most interesting prediction is artenimol, an antimalarial agent targeting ZFP62, one of our newly identified COVID-19-related genes. This drug is a derivative of artemisinin drugs that are already under clinical investigation for their potential role in the treatment of COVID-19. Our results demonstrate further applicability of the iCell framework for integrative comparative studies of human diseases.

Network neighbors of viral targets and differentially expressed genes in COVID-19 are drug target candidates.

The COVID-19 pandemic is raging. It revealed the importance of rapid scientific advancement towards understanding and treating new diseases. To address this challenge, we adapt an explainable artificial intelligence algorithm for data fusion and utilize it on new omics data on viral-host interactions, human protein interactions, and drugs to better understand SARS-CoV-2 infection mechanisms and predict new drug-target interactions for COVID-19. We discover that in the human interactome, the human proteins targeted by SARS-CoV-2 proteins and the genes that are differentially expressed after the infection have common neighbors central in the interactome that may be key to the disease mechanisms. We uncover 185 new drug-target interactions targeting 49 of these key genes and suggest re-purposing of 149 FDA-approved drugs, including drugs targeting VEGF and nitric oxide signaling, whose pathways coincide with the observed COVID-19 symptoms. Our integrative methodology is universal and can enable insight into this and other serious diseases.