Identification of a broad-spectrum flavivirus inhibitor targeting NS2A, a previously unidentified target
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Flaviviruses, such as dengue virus (DENV), Zika virus (ZIKV), West Nile virus (WNV), Japanese encephalitis virus (JEV), and yellow fever virus (YFV), constitute a significant public health concern with billions of people at risk of infection. Climate change and the expanding geographical distribution of mosquito vectors transmitting flaviviruses have increased their potential to cause large-scale disease outbreaks. The frequency and severity of disease outbreaks highlights the urgent need for a broad-spectrum antiviral agent targeting flaviviruses. In this work, we conducted a comprehensive morphological profiling of approximately 200,000 small molecules through a fluorescence-based high-content imaging platform, which led to the identification of a singular small molecule exhibiting broad-spectrum activity against flaviviruses. Subsequent hit deconvolution against DENV serotype 2 (DENV-2) revealed NS2A as a novel therapeutic target and suggested a mechanism whereby the identified small molecule inhibits the interaction between NS2A and the prM protein, revealing a previously uncharacterized antiviral mechanism of action.
