Target validation and in vivo testing of a broad-spectrum antiviral

Dengue virus (DENV) and other flaviviruses are human pathogens that cause significant disease. About 40% of the world lives in areas with substantial risk of DENV transmission. Up to 100 million people are infected annually with an estimated 500,000 hospitalizations and 20,000 deaths due to dengue hemorrhagic fever and dengue shock syndrome2. DENV presents a long-standing challenge for vaccine development due to antigenic diversity of the four DENV serotypes and the propensity of non-protective antibodies to enhance infection and disease severity4. There are no specific antivirals to counteract DENV.

We discovered QL47 and related tricyclic quinolones as potent covalent, host-targeted antivirals with broadspectrum activity against DENV and other RNA viruses of biomedical significance. Due to their broad-spectrum activity against the Flaviviridae and other viruses and their high natural barrier to resistance these compounds are of interest as antivirals. We have performed medicinal chemistry optimization to generate YKL-04-085, a candidate suitable for testing antiviral efficacy in vivo and have also performed chemoproteomic experiments to

identify the cellular targets responsible for antiviral activity. We propose to validate the antiviral target(s) of QL47/YKL-04-085 and to evaluate the antiviral activity of YKL-04-085 in a murine model of viral infection.