Identification of Nifurtimox and Chrysin as Anti-Influenza Virus Agents by Clinical Transcriptome Signature Reversion

The rapid development in the field of transcriptomics provides remarkable biomedical insights for drug discovery. In this study, a transcriptome signature reversal approach was conducted to identify the agents against influenza A virus (IAV) infection through dissecting gene expression changes in response to disease or compounds’ perturbations. Two compounds, nifurtimox and chrysin, were identified by a modified Kolmogorov–Smirnov test statistic based on the transcriptional signatures from 81 IAV-infected patients and the gene expression profiles of 1309 compounds. Their activities were verified in vitro with half maximal effective concentrations (EC(50)s) from 9.1 to 19.1 μM against H1N1 or H3N2. It also suggested that the two compounds interfered with multiple sessions in IAV infection by reversing the expression of 28 IAV informative genes. Through network-based analysis of the 28 reversed IAV informative genes, a strong synergistic effect of the two compounds was revealed, which was confirmed in vitro. By using the transcriptome signature reversion (TSR) on clinical datasets, this study provides an efficient scheme for the discovery of drugs targeting multiple host factors regarding clinical signs and symptoms, which may also confer an opportunity for decelerating drug-resistant variant emergence.