The World Health Organization estimates dengue viruses (DENV) infect 50-100 million people worldwide every year, of which 500,000 develop severe life-threatening disease. It causes approximately 25,000 deaths annually. Despite extensive research, there are not yet any approved vaccines or therapeutics commercially available to prevent or treat DENV infection. SIGA screened a 200,000 small molecule library using a whole virus assay and identified four series of compounds. Each series was evaluated for its chemical tractability, potency and selectivity. Preliminary structure-activity relationship (SAR) studies resulted in two lead series. Compounds in both series have shown efficacy in a sub-lethal murine model of DENV infection with the ability to significantly reduce viremia and viral load in target organs compared to vehicle-treated controls. Further optimizations considerably improved the potency against all four dengue serotypes and ADME properties. Compound resistances for ST-148 and ST-610 were mapped to the DENV capsid (C) gene and the NS3 helicase domain respectively. Ultimately a lead candidate was selected for preclinical development.tag 

Identification and optimization of novel dengue virus inhibitors

247th National Meeting (2014)

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