Kinase inhibitors tyrphostin 9 and rottlerin block early steps of rabies virus cycle

Rabies virus (RABV) is a neurotropic virus that causes fatal encephalitis in humans and animals and still kills up to 59,000 people worldwide every year. To date, only preventive or post-exposure vaccination protects against the disease but therapeutics are missing. After screening a library of 80 kinases inhibitors, we identified two compounds as potent inhibitors of RABV infection: tyrphostin 9 and rottlerin. Mechanism of action studies show that both inhibitors interfere with an early step of viral cycle and can prevent viral replication. In presence of tyrphostin 9, the viral entry through endocytosis is disturbed leading to improper delivery of viral particles in cytoplasm, whereas rottlerin is inhibiting the transcription, most likely by decreasing intracellular ATP concentration, and therefore the replication of the viral genome.