Abstract
SARS-CoV-2 hijacks the host cell transcriptional machinery to induce a phenotypic state amenable to its replication. Here we show that analysis of Master Regulator proteins representing mechanistic determinants of the gene expression signature induced by SARS-CoV-2 in infected cells revealed coordinated inactivation of Master Regulators enriched in physical interactions with SARS-CoV-2 proteins, suggesting their mechanistic role in maintaining a host cell state refractory to virus replication. To test their functional relevance, we measured SARS-CoV-2 replication in epithelial cells treated with drugs predicted to activate the entire repertoire of repressed Master Regulators, based on their experimentally elucidated, context-specific mechanism of action. Overall, 15 of the 18 drugs predicted to be effective by this methodology induced significant reduction of SARS-CoV-2 replication, without affecting cell viability. This model for host-directed pharmacological therapy is fully generalizable and can be deployed to identify drugs targeting host cell-based Master Regulator signatures induced by virtually any pathogen.
【초록키워드】 SARS-CoV-2, therapy, drug, Replication, Protein, pathogen, viability, inactivation, virus replication, epithelial cells, methodology, mechanism of action, SARS-CoV-2 replication, cell viability, Interaction, Analysis, SARS-CoV-2 proteins, epithelial cell, host cell, reduction, determinant, infected cells, phenotypic, gene expression signature, infected cell, regulator, pharmacological, Host, physical, effective, Cell, transcriptional, predicted, identify, treated, functional, induce, representing, activate, without affecting, drugs targeting, repressed, 【제목키워드】 viral infection, pharmacological, transcriptional,