Novel Antiviral Agents Targeting Zika and Dengue Virus

Zika virus (ZIKV) and closely related dengue virus (DENV) are major human pathogens. ZIKV and DENV are transmitted by Aedes mosquitoes in the tropical and subtropical regions, where approximately 3 billion people or 40% of world population live and are at risk of these infections. ZIKV has caused three major outbreaks on Yap Island (2007), in French Polynesia (2013), and in Brazil and other American countries (2015-2016). Several million people in 48 Pan-American countries and territories have been infected, showing symptoms including fever, rashes and conjunctivitis. Although most people recover in a few days, ZIKV infection has been found to cause a 20-fold increased incidence of serious neurological diseases, such as Guillain-Barré syndrome and >4,000 cases of microcephaly (small brain/head) and other neurological defects in newborns. WHO announced ZIKV is a "Public Health Emergency". It is estimated that DENV infects ~400 million people per year with 100 million developing symptoms including fever, headache, rash, conjunctivitis and muscle and joint pain. ~500,000 cases/year progress to serious and potentially life-threatening dengue hemorrhagic fever or shock syndrome, with approximately 22,000 deaths annually, mostly among children. Except for mosquito control, there have been no available antiviral drugs to prevent or treat ZIKV and DENV infections. There is therefore a pressing need to find effective antiviral agents against ZIKV and DENV. In this project, we propose to perform medicinal chemistry and structure-activity relationship (SAR) studies to develop potent anti-ZIKV/DENV compounds (Specific Aim 1) and use chemical biology, biochemical, and cell biology methods to identify the protein target of these compounds.