Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

Abstract

Rabies virus (RABV) constitutes a major social and economic burden associated with 60,000 deaths annually worldwide. Although pre-and post-exposure treatment options are available, they are efficacious only when initiated prior to 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 RNAdependent RNA polymerase complex as a promising target for direct-acting broad-spectrum RABV inhibitors.

Nouveaux aspects de la lutte contre la rage

“…Actuellement, la seule approche thérapeutique décrite reste le protocole Milwaukee. Après plusieurs modifications depuis sa première utilisation en 2004, aujourd’hui il comprend, entre autres, l’induction d’un coma artificiel et l’injection de kétamine et d’amantadine (deux antagonistes compétitifs des récepteurs NMDA qui empêcheraient la libération des particules virales) [1] , [8] , [64] . Néanmoins, son efficacité est discutable, car au moins 31 échecs documentés ont été signalés [7] , [8] .…”

Virology Downunder, a meeting commentary from the 2019 Lorne Infection and Immunity Conference, Australia

“…Endemic dog rabies results in an ongoing risk to humans in many resource-limited countries, whereas rabies in wildlife is important in North America and Europe [9]. Requirement for an uninterrupted vaccine cold chain and the high cost of the immunoglobulin component of rabies prophylaxis therapies substantiate the unmet need for novel RABV-specific antivirals [10]. Furthermore, the pathogenesis of RABV relating to viral replication in neurons is not fully understood [11].…”

Transcriptional Control and mRNA Capping by the GDP Polyribonucleotidyltransferase Domain of the Rabies Virus Large Protein

“…Rabies virus (RABV) is a nonsegmented negative-strand (NNS) RNA virus belonging to the Lyssavirus genus of the Rhabdoviridae family in the order Mononegavirales (reviewed in References [1,2,3]). RABV is transmitted to humans from infected animals, mainly domestic dogs, through their saliva by biting or scratching, and causes an acute, fatal neurological disease, called rabies [2,3,4]. Although rabies is preventable by vaccination prior to or immediately after exposure, there are currently no established therapeutic countermeasures once patients are symptomatic [4].…”

“…RABV is transmitted to humans from infected animals, mainly domestic dogs, through their saliva by biting or scratching, and causes an acute, fatal neurological disease, called rabies [2,3,4]. Although rabies is preventable by vaccination prior to or immediately after exposure, there are currently no established therapeutic countermeasures once patients are symptomatic [4]. RABV kills more than 50,000 people each year worldwide [5,6], posing continuing threats to human health, especially in developing countries with lower vaccination coverage in domestic dogs.…”