Development and mechanism of action of novel inhibitors of rabies virus replication.

Rabies viurs infection causes encephalomyelitis in humans with a nearly 100% case fatality rate. Current strategies of post-exposure prophylaxis treatment(PEP) are highly effective and involve vaccination together with infiltration of the wound with anti-rabies immunoglobulins(RIG's). Each year ~60,000 people succumb because of rabies and the societal cost worldwide is estimated to be in excess of US$6 billion. However, effective antivirals could also be used in PEP to replace the use of RIG's which are in short supply throughout the world. To screen the more efficient anti-rabies drugs we will further develop the rabies virus assay technology to create a platform for antiviral drug discovery. After hit confirmation, the different anti-rabies molecules discovered will be profiled on several aspects: 1. The activity of the molecules in vitro under different condition of viral loads, cell lines, on different lyssa-virus strains and other virus species. 2. To determine the target of the antivirals. 3. Selected candidate antivirals and/or combinations of antivirals with potent activity and drug-like properties will be explored further in animal models of efficacy. Taken together, this work will show the potency of the development of novel agents against RABV.