Novel Antiviral Agents Targeting Zika and Dengue Virus

Zika virus (ZIKV) and closely related dengue virus (DENV) are major human pathogens. ZIKV and DENV aretransmitted by Aedes mosquitoes in the tropical and subtropical regions where approximately 3 billion peopleor 40% of world population live and are at risk of these infections. ZIKV has caused three major outbreaks onYap Island (2007) in French Polynesia (2013) and in Brazil and other American countries (2015-2016). Severalmillion people in 48 Pan-American countries and territories have been infected showing symptoms includingfever rashes and conjunctivitis. Although most people recover in a few days ZIKV infection has been found tocause a 20-fold increased incidence of serious neurological diseases such as Guillain-Barr syndromeand >4000 cases of microcephaly (small brain/head) and other neurological defects in newborns. WHOannounced ZIKV is a Public Health Emergency. It is estimated that DENV infects ~400 million people per yearwith 100 million developing symptoms including fever headache rash conjunctivitis and muscle and joint pain. ~500000 cases/year progress to serious and potentially life-threatening dengue hemorrhagic fever or shocksyndrome with approximately 22000 deaths annually mostly among children. Except for mosquito control therehave been no available antiviral drugs to prevent or treat ZIKV and DENV infections. There is therefore a pressingneed to find effective antiviral agents against ZIKV and DENV. In this project we propose to perform medicinalchemistry 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 ofthese compounds.