Network-based Drug Repurposing for Human Coronavirus

Yadi Zhou; Yuan Hou; Jiayu Shen; Yin Huang; William Martin; Feixiong Cheng

To further validate the 135 repurposable drugs against HCoVs, we first performed gene set enrichment analysis (GSEA) using transcriptome data of MERS-CoV and SARS-CoV infected host cells (see Methods). These transcriptome data were used as gene signatures for HCoVs. Additionally, we downloaded the expression data of drug-treated human cell lines from the Connectivity Map (CMAP) database [33] to obtain drug-gene signatures. We calculated a GSEA score (see Methods) for each drug and used this score as an indication of bioinformatics validation of the 135 drugs. Specifically, an enrichment score (ES) was calculated for each HCoV data set, and ES > 0 and P < 0.05 (permutation test) was used as cut-off for a significant association of gene signatures between a drug and a specific HCoV. The GSEA score, ranging from 0 to 3, is the number of data sets that met these criteria for a specific drug. Mesalazine (an approved drug for inflammatory bowel disease), sirolimus (an approved immunosuppressive drug), and equilin (an approved agonist of the estrogen receptor for menopausal symptoms) achieved the highest GSEA scores of 3, followed by paroxetine and melatonin with GSEA scores of 2. We next selected 16 potential repurposable drugs ( Figure 5A and Table 1 ) against HCoVs using subject matter expertise based on a combination of factors: (i) strength of the network-predicted associations (a smaller network proximity score in Supplementary Table S4 ); (ii) validation by GSEA analyses;