West Nile virus - a re-emerging global threat: recent advances in vaccines and drug discovery

Abstract

West Nile virus (WNV) is an emerging mosquito-borne pathogen and is posing significant global health challenge through climate change. WNV, transmitted between birds and Culex mosquitoes, has significantly expanded northward in recent years, leading to outbreaks across Europe and North America. This review explores the recent advancements and therapeutic strategies targeting WNV's structural and non-structural (NS) proteins, which play critical roles in viral replication and pathogenesis. Promising candidates include peptide-based inhibitors, monoclonal antibodies, and small molecules that disrupt protein-protein interactions. Most of current findings are derived from in silico methods or in vitro assays, with limited validation through in vivo studies. Although no vaccines are currently available for humans, several have been approved for horses, and development efforts are ongoing. The growing threat of WNV underscores the urgent need for validated antiviral therapies and scalable vaccines, especially considering its increasing geographic range and public health impact.

Keywords: NS3; NS5; West Nile virus; antiviral drug discovery; arbovirus; envelope protein; flavivirus; structural and non-structural protein targets.

Figure 1

Life cycle of the West Nile virus and key drug targets. The WNV initiates infection by binding to an as-yet unidentified receptor on the host cell surface. Entry into the host cell is mediated via clathrin-dependent endocytosis. Following internalisation, the virus fuses with the vesicular membrane, releasing the gRNA into the cytoplasm. The gRNA is translated into a polyprotein precursor, which undergoes proteolytic cleavage to produce structural proteins (C, prM, E) and non-structural proteins (NS). The non-structural proteins form the replication complex, facilitating the synthesis of new gRNA. Structural proteins and replicated gRNA are assembled into nascent virions within the ER. The partially assembled virions are encapsidated and transported through the ERGIC to the Golgi apparatus. Final virion maturation occurs in the vesicles that are transported to the cell membrane, where furin cleaves prM to M, before the release of the newly formed infectious virus particles, which can now infect additional host cells. Several therapeutic targets have been identified along this pathway, such as the E protein, NS3 protease, NS5 RdRp, and the NS3-NS5 interaction interface. C, Capsid protein; E, Envelope protein; ER, Endoplasmic Reticulum; ERGIC, ER-Golgi intermediate compartment; gRNA, genomic RNA; NS, Non-Structural protein; prM, pre-Membrane protein; RdRp, RNA-dependent RNA polymerase; WNV, West Nile Virus. The figure was created with the help of BioRender.com.