Antiviral drug research for Japanese encephalitis: an updated review

Abstract

Japanese encephalitis (JE) caused by the Japanese encephalitis virus (JEV) is one of Asia's most common viral encephalitis. JEV is a flavivirus, common in rural and sub-urban regions of Asian countries. Although only 1% of JEV-infected individuals develop JE, there is a 20–30% chance of death among these individuals and possible neurological sequelae post-infection. No licensed anti-JE drugs are currently available, despite extensive efforts to develop them. Literature search was performed using databases such as PubMed Central, Google Scholar, Wiley Online Library, etc. using keywords such as Japanese encephalitis virus, antiviral drugs, antiviral drug screening, antiviral drug targets, etc. From around 230 papers/abstracts and research reviews retrieved and reviewed for this study, approximately 180 most relevant and important ones have been cited. Different approaches in drug testing and various antiviral drug targets explored so far have been thoroughly searched from the literature and compiled, besides addressing the future perspectives of the antiviral drug development strategies. Although the development of effective anti-JE drugs is an urgent issue, only supportive care is currently available. Recent advancements in understanding the biology of infection and new drug targets have been promising improvements. Despite hindrances such as the unavailability of a proper drug delivery system or a treatment regimen irrespective of the stage of infection, several promising anti-JE candidate molecules are in different phases of clinical trials. Nonetheless, efficient therapy against JEV is expected to be achieved with drug combinations and a highly targeted drug delivery system soon. Graphical abstract

Antiviral and anti‐inflammatory activity of natural compounds against Japanese encephalitis virus via inhibition of NS5 protein and regulation of key immune and inflammatory signaling pathways

“…These proteins are crucial for the entry, maturation, replication, and release of virus in the host cells 6 . Envelope, nonstructural protein‐1, JEV protease, helicase/nucleoside triphosphatase, and RNA‐dependent RNA polymerase (NS5) of JEV have been targeted to design direct antiviral agents against JEV 7 …”

“…6 Envelope, nonstructural protein-1, JEV protease, helicase/nucleoside triphosphatase, and RNA-dependent RNA polymerase (NS5) of JEV have been targeted to design direct antiviral agents against JEV. 7 Therefore, in pursuit of anti-JEV agents, we searched the Indian Medicinal Plants, Phytochemistry, and Therapeutics (IMPPAT) and PubMed databases for medicinal plants having "antiviral" and "antiinflammatory" activities. 8 We have found that Andrographis paniculata, Berberis lycium, Curcuma longa, and Vitis vinifera possess both activities, and the key chemical constituents present in these plants were identified as andrographolide, berberine, curcumin, resveratrol, and retinoic acid, respectively (Table S1).…”

Recent advances to overcome the burden of Japanese encephalitis: A zoonotic infection with problematic early detection

“…Most of the studies performed by administering the potential agents at the early stages of the infection failed to give a promising therapy. 131 Pentoxifylline which is an anti-TNF agent has shown 100% recovery of a mice model at a dose value of 200 mg/ kg. 132 Another such drug is arctigenin which is lignan of Asteraceae plants that has also shown 100% recovery at a dose of 20 mg/kg but only with immediate (1 day of infection) administration.…”

“…Coming to the therapy for encephalitis, initially the agents with profound efficacy against the JE infection were very few, due to the infection complexity and difficulties in understanding the disease invasion. Most of the studies performed by administering the potential agents at the early stages of the infection failed to give a promising therapy 131 . Pentoxifylline which is an anti‐TNF agent has shown 100% recovery of a mice model at a dose value of 200 mg/kg 132 .…”

Recent Advances in Antivirals for Japanese Encephalitis Virus

“…Humans and horses are considered to be dead-end hosts [ 6 ]. The prevalence of JEV shows specific distribution characteristics on the geographical scale, seasonal scale, climate scale, and population scale [ 7 ]. In temperate and subtropical regions, populations in agricultural areas are the primary populations exposed to JEV with the onset of the rainy season, among which, unvaccinated populations and children are at high risk of JEV infection.…”