Exploring RNA G-quadruplex in the rabies virus genome and its potential against RABV infection

Rabies virus (RABV) is a prototypical neurotropic RNA virus that can cause rabies with an almost 100% fatality rate. Despite great efforts having been made to identify an effective therapeutic target of rabies, the host factors involved in RABV infection and the underlying mechanisms remain poorly understood. There are no effective drug targets for human rabies to date. Therefore, a better understanding of rabies pathogenesis and exploring new targets for antiviral treatments are crucial and urgent. In this study, we identify the presence of G-quadruplex (G4) in the RABV genome and uncover a novel role of G4 in RABV infection, in which stabilization of G4 can suppress G protein translation and viral replication. By systematic screening of 10 pairs of triplex metallohelices (designated as M1-M10), we found that one enantiomer of a pair of glycoconjugated metallohelices (Λ-M10) has exceptional RABV G4-stabilizing ability. Further studies show that Λ-M10 exhibits potent antiviral activity against RABV by targeting viral RNA G4s while maintaining minimal cytotoxicity in RABV-infected cell lines. More interestingly, having a nanosized structure and glycoconjugated modifications, M10 could cross the blood-brain barrier, supporting the potential in clinical therapy for RABV infection. Our findings elucidate the presence of G4 in the RABV genome, which can be targeted by G4 ligands such as metallohelices to suppress crucial G protein translation and viral replication, a previously unrecognized mechanism against RABV infection.