Abstract
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 (EC50s) 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.
Highlights
Influenza, referred to as “flu”, is a contagious respiratory illness caused by influenza A or B virus infection, which causes severe seasonal epidemics worldwide, with 3–5 million severe cases and 290,000–650,000 deaths annually [1]
The classical drug discovery process often starts with target identification and validation, followed by high-throughput screening (HTS) or small molecular design based on receptors and ligands to acquire hit compounds
The transcriptome signature reversion (TSR) strategy was constructed based on the rapid development of omics technologies and application of omics data, of which the major advantage is that the compounds drawing the disease state back to normal were considered as potential active therapeutic agents
Summary
Referred to as “flu”, is a contagious respiratory illness caused by influenza A or B virus infection, which causes severe seasonal epidemics worldwide, with 3–5 million severe cases and 290,000–650,000 deaths annually [1]. Six regiments have been used for anti-influenza therapy through targeting three viral proteins: matrix-2 (M2) proton channel, neuraminidase (NA), and cap-dependent endonuclease (CEN) [3]. The emergence of drug-resistant variants is the major challenge for using virus-targeted drugs, as adamantanes were eliminated for anti-influenza clinical therapy and neuraminidaseinhibitor-resistant viruses were reported [4,5,6], resulting in urgent demand for novel anti-influenza agents’ development. The rapid development of the transcriptome database provides new biomedical insights for drug discovery through dissecting host gene expression fluctuations in response to disease and compounds’ perturbations [7], which is later being called transcriptome signature reversion (TSR). The approach of TSR has been implemented to explore candidates for Alzheimer’s disease [12], spontaneous preterm birth [13], cancer [14], aging [15], etc
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