Abstract
The outbreak of West Nile virus (WNV) in 1999 in the USA, and its continued spread throughout the Americas, parts of Europe, the Middle East and Africa, underscored the need for WNV antiviral development. Here, we review the current status of WNV drug discovery. A number of approaches have been used to search for inhibitors of WNV, including viral infection-based screening, enzyme-based screening, structure-based virtual screening, structure-based rationale design, and antibody-based therapy. These efforts have yielded inhibitors of viral or cellular factors that are critical for viral replication. For small molecule inhibitors, no promising preclinical candidate has been developed; most of the inhibitors could not even be advanced to the stage of hit-to-lead optimization due to their poor drug-like properties. However, several inhibitors developed for related members of the family Flaviviridae, such as dengue virus and hepatitis C virus, exhibited cross-inhibition of WNV, suggesting the possibility to re-purpose these antivirals for WNV treatment. Most promisingly, therapeutic antibodies have shown excellent efficacy in mouse model; one of such antibodies has been advanced into clinical trial. The knowledge accumulated during the past fifteen years has provided better rationale for the ongoing WNV and other flavivirus antiviral development.
Highlights
West Nile virus (WNV) has an enveloped virion of about 50 nm in diameter, and comprises a lipid bilayer that surrounds a nucleocapsid with a single-stranded, positive-sense RNA genome of approximately 11,000 nucleotides
Compared with HCV or dengue virus (DENV), the effort for WNV drug discovery is much lower. This may be due to the perception that there is not an urgent need for antivirals against this disease
Given the mutability of the virus, in particular for enhanced neuroinvasiveness, it is possible that new waves of WNV outbreak may take place from newly emerging virulent isolates
Summary
West Nile virus (WNV) has an enveloped virion of about 50 nm in diameter, and comprises a lipid bilayer that surrounds a nucleocapsid with a single-stranded, positive-sense RNA genome of approximately 11,000 nucleotides Both the 5’ and 3’ noncoding regions of the genome form extensive secondary structures, which are important for translation, RNA synthesis, and packaging [1,2,3]. Several of the nonstructural proteins, including NS2A, NS2B, NS4A, and NS4B, are transmembrane proteins that have no identified enzymatic activities, but are essential for formation of the active replication complex [8,9] They have been shown to inhibit one or more components of the innate immune response against viral infection [10]. This article reviews the latest development in WNV drug discovery and the challenges/opportunities ahead
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