Op weg naar nieuwe strategieën voor post-expositie profylaxe en behandeling van hondsdolheid

Rabies virus (RABV), a negative-stranded RNA virus of the Lyssavirus genus, causes ~60,000 deaths annually. While post-exposure prophylaxis (PEP) is effective, challenges like cold chain requirements and high costs limit its accessibility in endemic regions. Moreover, once symptoms appear, rabies is nearly 100% fatal, with no available antiviral treatment. This study aims to develop alternative antiviral strategies. A physiologically relevant swine muscle model was established to mimic RABV infection, where Urtica dioica agglutinin (UDA) was found to block viral entry. Then, human brain spheroids were used to study RABV infection and assess antivirals; remdesivir inhibited replication but failed to improve survival in infected mice. A high-throughput screening assay identified salinomycin as an RABV entry inhibitor. Screening of 118,400 small molecules led to the discovery of two promising inhibitors, which target the viral polymerase (L) protein. In conclusion, this work contributes to RABV drug discovery by (i) developing physiologically relevant infection models, (ii) establishing a high-throughput antiviral assay, (iii) demonstrating that entry inhibitors can block RABV replication in muscle tissue, and (iv) identifying novel non-nucleoside inhibitors of viral replication. These findings may serve as a foundation for future rabies drug development.