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Review
. 2024 Jan 28;16(2):202.
doi: 10.3390/v16020202.

Current Advances in Japanese Encephalitis Virus Drug Development

Jiao Guo  1 , Yunqi Mi  1 , Yan Guo  2 , Yang Bai  1 , Meihua Wang  3 , Wei Wang  4 , Yang Wang  1
Affiliations
Review

Current Advances in Japanese Encephalitis Virus Drug Development

Jiao Guo et al. Viruses. .

Abstract

Japanese encephalitis virus (JEV) belongs to the Flaviviridae family and is a representative mosquito-borne flavivirus responsible for acute encephalitis and meningitis in humans. Despite the availability of vaccines, JEV remains a major public health threat with the potential to spread globally. According to the World Health Organization (WHO), there are an estimated 69,000 cases of JE each year, and this figure is probably an underestimate. The majority of JE victims are children in endemic areas, and almost half of the surviving patients have motor or cognitive sequelae. Thus, the absence of a clinically approved drug for the treatment of JE defines an urgent medical need. Recently, several promising and potential drug candidates were reported through drug repurposing studies, high-throughput drug library screening, and de novo design. This review focuses on the historical aspects of JEV, the biology of JEV replication, targets for therapeutic strategies, a target product profile, and drug development initiatives.

Keywords: JEV; antiviral drug development; flaviviruses.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 2
Figure 2
JEV structural organisation and genome representation. (A) The nucleocapsid (genomic RNA within a viral capsid protein shell) is surrounded by a lipid bilayer containing viral proteins M and E. (B) The JEV genome is approximately 11 kb in length, is capped at the 5′ end, and has no 3′ poly (A) tail. Viral structural genes (represented by a red rectangle) and non-structural genes (represented by a blue rectangle) encoded in the (+)-strand RNA genome are shown. The viral proteins (C, PrM, E, NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5) are produced by processing the polyprotein using either a cellular signalase (indicated by black arrows) or the viral NS2A/NS3 protease (represented by red arrows). The PrM protein undergoes further processing by host furin (represented by a blue arrow) to generate glycosylated M protein, a constituent of the flavivirus mature virion. (C) A diagram showing the arrangement of the JEV polyprotein in the ER membrane is presented. The arrangement of JEV’s structural and non-structural proteins in relation to the cytosol and ER lumen is illustrated. The proteins of JEV are distributed in the cytoplasm (NS3 and NS5), in the ER lumen (NS1), and in the ER membrane (C, PrM/M, E, NS2A, NS2B, NS4A, and NS4B). The figure is adapted from Ray et al., 2006 [55], Sharma et al., 2021 [19], Kumar et al., 2022 [56], and Pierson et al., 2020 [39].
Figure 1
Figure 1
Geographical distribution of JEV infection. Map reproduced from Srivastava et al., 2023 [14], Sharma et al., 2021 [19], Mackenzie et al., 2022 [11], van den Hurk et al., 2009 [12], and Mulvey et al., 2021 [25].
Figure 3
Figure 3
JEV life cycle. Virions are adsorbed onto the host cellular membrane and then enter the cell via receptor-mediated endocytosis. A low-pH environment in the endosome initiates the rearrangement of the viral envelope, culminating in membrane fusion and the release of the genome into the cytoplasm. The positive-sense viral RNA is translated, resulting in a single polyprotein that is cleaved into structural and non-structural proteins. Viral replication is facilitated by a specialized compartment (comprising NS5, the RdRp, and other viral non-structural proteins and multiple host factors). This compartment transcribes the positive-strand genomic RNA into a negative-strand RNA, which is then employed as a template to produce progeny (+)-strand genomes. After replication, the genome of the virus is encapsidated by C protein and transported to the ER, where the nucleocapsid is enveloped by a lipid bilayer in which the PrM and E proteins are embedded. Immature virions, consisting of genomic RNA, PrM-E heterodimers, and C, travel through the trans-Golgi network and mature via furin cleavage. This figure was originally created using BioRender.com, accessed on 20 October 2023.
Figure 4
Figure 4
JEV entry inhibitors. This figure was originally created using KingDraw software 3.1.0.20.
Figure 5
Figure 5
JEV RdRp inhibitors. This figure was originally created using KingDraw software 3.1.0.20.
Figure 6
Figure 6
JEV protease inhibitors. This figure was originally created using KingDraw software 3.1.0.20.
Figure 7
Figure 7
JEV inhibitors derived from natural products. This figure was originally created using KingDraw software 3.1.0.20.
Figure 8
Figure 8
Host-directed JEV antivirals. This figure was originally created using KingDraw software 3.1.0.20.
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