Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

Rabies virus (RABV) constitutes a major social and economic burden associated with 60 000 deaths annually worldwide. Although pre-exposure and post-exposure treatment options are available, they are efficacious only when initiated before the onset of clinical symptoms. Aggravating the problem, the current RABV vaccine does not cross-protect against the emerging zoonotic phylogroup II lyssaviruses. A requirement for an uninterrupted cold chain and high cost of the immunoglobulin component of rabies prophylaxis generate an unmet need for the development of RABV-specific antivirals. We discuss desirable anti-RABV drug profiles, past efforts to address the problem and inhibitor candidates identified, and examine how the rapidly expanding structural insight into RABV protein organization has illuminated novel druggable target candidates and paved the way to structure-aided drug optimization. Special emphasis is given to the viral RNA-dependent RNA polymerase complex as a promising target for direct-acting broad-spectrum RABV inhibitors.