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Statin-mediated disruption of Rho GTPase prenylation and activity inhibits respiratory syncytial virus infection

ABSTRACT: Respiratory syncytial virus (RSV) is a leading cause of severe respiratory tract infections in children. To uncover new antiviral therapies, we developed a live cell-based high content screening approach for rapid identification of RSV inhibitors and characterized five drug classes which inhibit the virus. Among the molecular targets for each hit, there was a strong functional enrichment in lipid metabolic pathways. Modulation of lipid metabolites by statins, a key hit from our screen, decreases the production of infectious virus through a combination of cholesterol and isoprenoid-mediated effects. Notably, RSV infection globally upregulates host protein prenylation, including the prenylation of Rho GTPases. Treatment by statins or perillyl alcohol, a geranylgeranyltransferase inhibitor, reduces infection in vitro. Of the Rho GTPases assayed in our study, a loss in Rac1 activity strongly inhibits the virus through a decrease in F protein surface expression. Our findings provide new insight into the importance of host lipid metabolism to RSV infection and highlight geranylgeranyltransferases as an antiviral target for therapeutic development. Malhi et al. conduct a high-throughput screen to identify inhibitors of respiratory syncytial virus (RSV). They find that statins inhibit post-entry events in the replicative cycle of RSV through a combination of cholesterol and isoprenoid-mediated effects, the latter involving a loss of Rho GTPase activity via disruption of protein prenylation.

SUBMITTER: Malhi M

PROVIDER: S-EPMC8556396 | biostudies-literature |

REPOSITORIES: biostudies-literature

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