Systems Biology-Based Investigation of Cellular Antiviral Drug Targets Identified by Gene-Trap Insertional Mutagenesis

Abstract

Viruses require host cellular factors for successful replication. A comprehensive systems-level investigation of the virus-host interactome is critical for understanding the roles of host factors with the end goal of discovering new druggable antiviral targets. Gene-trap insertional mutagenesis is a high-throughput forward genetics approach to randomly disrupt (trap) host genes and discover host genes that are essential for viral replication, but not for host cell survival. In this study, we used libraries of randomly mutagenized cells to discover cellular genes that are essential for the replication of 10 distinct cytotoxic mammalian viruses, 1 gram-negative bacterium, and 5 toxins. We herein reported 712 candidate cellular genes, characterizing distinct topological network and evolutionary signatures, and occupying central hubs in the human interactome. Cell cycle phase-specific network analysis showed that host cell cycle programs played critical roles during viral replication (e.g. MYC and TAF4 regulating G0/1 phase). Moreover, the viral perturbation of host cellular networks reflected disease etiology in that host genes (e.g. CTCF, RHOA, and CDKN1B) identified were frequently essential and significantly associated with Mendelian and orphan diseases, or somatic mutations in cancer. Computational drug repositioning framework via incorporating drug-gene signatures from the Connectivity Map into the virus-host interactome identified 110 putative druggable antiviral targets and prioritized several existing drugs (e.g. ajmaline) that may be potential for antiviral indication (e.g. anti-Ebola). In summary, this work provides a powerful methodology with a tight integration of gene-trap insertional mutagenesis testing and systems biology to identify new antiviral targets and drugs for the development of broadly acting and targeted clinical antiviral therapeutics.

Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2

“…However, experimental approaches for drug repurposing is costly and time-consuming 12 . Computational approaches offer novel testable hypotheses for systematic drug repositioning [9][10][11]13,14 . However, traditional structure-based methods are limited when threedimensional (3D) structures of proteins are unavailable, which, unfortunately, is the case for the majority of human and viral targets.…”

Treating the host response to emerging virus diseases: lessons learned from sepsis, pneumonia, influenza and Ebola

“…The search for ways to treat patients with Ebola virus disease is still dominated by a focus on drugs that target the virus (261,262). The Ebola "lessons learned" reports call for huge investments that (it is hoped) will lead to the discovery of novel therapeutic agents (223)(224)(225).…”

A review on the antagonist Ebola: A prophylactic approach

“…Systems biology based antiviral drug studies have tremendously helped in the identification of new antiviral candidates. Cheng et al [31] have proposed an integrated approach to determine new antiviral candidates for the existing drugs by adding drug-gene patterns into the virus-host interactome. Using systems biology analysis they have determined three molecule drugs namely, Ajmaline, Piroxicam and Azlocillin, as the new drug candidates for anti-Ebola virus treatment.…”