Ribavirin-related compounds exert in vitro inhibitory effects toward rabies virus

Abstract

Rabies remains an invariably fatal neurological disease despite the availability of a preventive vaccination and post-exposure prophylaxis that must be immediately administered to the exposed individual before symptom onset. There is no effective medication for treatment during the symptomatic phase. Ribavirin, a guanine nucleoside analog, is a potent inhibitor of rabies virus (RABV) replication in vitro but lacks clinical efficacy. Therefore, we attempted to identify potential ribavirin analogs with comparable or superior anti-RABV activity. Antiviral activity and cytotoxicity of the compounds were initially examined in human neuroblastoma cells. Among the tested compounds, two exhibited a 5- to 27-fold higher anti-RABV activity than ribavirin. Examination of the anti-RABV mechanisms of action of the compounds using time-of-addition and minigenome assays revealed that they inhibited viral genome replication and transcription. Addition of exogenous guanosine to RABV-infected cells diminished the antiviral activity of the compounds, suggesting that they are involved in guanosine triphosphate (GTP) pool depletion by inhibiting inosine monophosphate dehydrogenase (IMPDH). Taken together, our findings underline the potency of nucleoside analogs as a class of antiviral compounds for the development of novel agents against RABV.

Comparing clinical protocols for the treatment of human rabies: the Milwaukee protocol and the Brazilian protocol (Recife)

“…Amantadine is a synthetic antiviral agent that can inhibit viral replication by binding to the NMDA antagonist receptor 19 . This drug is also indicated in both analyzed protocols.…”

Anno 2021: Which antivirals for the coming decade?

“… 217 Some ribavirin analogues named EICAR and EICNR displayed increased in vitro activity (EC 50 = 0.9–3.8 μM) as inhibitors of viral replication and transcription, most likely via IMPDH inhibition, compared to ribavirin (EC 50 = 18.6 μM); however, a more systematic evaluation is needed to define their anti-RABV potential. 218 …”

Status of antiviral therapeutics against rabies virus and related emerging lyssaviruses

“…Small-molecule antivirals in general have the advantages of cost-effective manufacture -addressing supply concerns -as well as high shelf-stability, enabling developing countries to stock-pile life-saving supplies [42]. Currently, there are no small-molecule inhibitors licensed for therapeutic use, despite several attempts at discovery [41,[54][55][56][57][58][59][60][61][62]. Based on previous antiviral activity of phenolic compounds against viruses such as HIV, herpes simplex virus and influenza virus, 24 representatives of this class were tested against RABV.…”

“…Screening of several ribavirin analogs returned two compounds, EICAR and EICNR, that had superior antiviral potency in human neuroblastoma cells (EC 50 0.9 μM, and 3.8 μM, respectively), compared to the ribavirin EC 50 of 18.6 μM [57]. However, testing of these compounds was limited to the RABV vaccine strain, necessitating further examination in vivo against clinically-relevant pathogenic RABVs.…”