Carme Zambrana*1, Sam Windels1, Noël Malod-Dognin1, and Nataša Pržulj1,2,3
1 Barcelona Supercomputing Center (BSC), Barcelona 08034, Spain
2 Department of Computer Science, University College London, London WC1E 6BT, UK
3 ICREA, Pg. Lluis Companys 23, 08010 Barcelona, Spain
carme.zambrana [at] bsc.es
Abstract
Viral infections continue to cause pandemics. Antiviral drugs are based on two strategies: targeting the viral proteins or the host proteins. The main limitations of antiviral drugs targeting viral proteins are their high ratio of drug resistance and their specificity to one virus. A rapid and effective way to overcome these limitations is by re-purposing existing drugs that target the host biological mechanisms used by the virus. Moreover, when these biological mechanisms are shared across different viruses (i.e., “pan-viral” disease mechanisms), the re-purposed drugs are good candidates for broad-spectrum viral treatments.
In our previous work, we investigated how the viral interactors (VIs) of SARS-CoV-2 and differentially expressed genes (DEGs) after COVID-19 infection are connected in the host interactome. We uncover that, in the host interactome, VIs and DEGs, while mostly disjoint, are indirectly connected by their neighbours (we termed them “common neighbours” (CN) genes). Furthermore, we found that the CN genes are key to COVID-19 mechanisms and promising targets for drug re-purposing.
Here, we expand our results to 13 viruses, uncovering “pan-viral” genes and re-purposing drugs for broad-spectrum viral treatments. First, we identify CN genes for five well-studied viruses and approximate their identification for viral infections without DEG data, uncovering disease genes for 13 viruses (8 without DEG data). Then, we find that the CNs are shared across viruses with significant enrichment in viral and immune system-related processes, showing our methodology’s capability to uncover “pan-viral” disease mechanisms. Finally, we predict new drug-target interactions to identify drugs targeting our “pan-viral” genes by using a two-step machine-learning model. The CNs allowed us to re-purpose drugs for treating viral infections by disrupting “pan-viral” disease mechanisms, paving the way for broad-spectrum drug re-purposing. Moreover, the CN genes can enable insight into other infectious diseases.
Keywords: omics data fusion, drug re-purposing, network biology
Acknowledgement: This project has received funding from the European Union’s EU Framework Programme for Research and Innovation Horizon 2020, Grant Agreement No 860895, the European Research Council (ERC) Consolidator Grant 770827, the Spanish State Research Agency and the Ministry of Science and Innovation MCIN grant PID2022-141920NB-I00 / AEI /10.13039/501100011033/ FEDER, UE, and the Department of Research and Universities of the Generalitat de Catalunya code 2021 SGR 01536.