Identification/Optimization of Novel Small Molecule Inhibitors of Zika Virus Infection

Abstract

The rate of Zika virus (ZIKV) infection has been increasing since the original 2014 re‐emergence of the virus in Brazil, and the World Health Organization has warned against potential ZIKV epidemics. Furthermore, ZIKV, a flavivirus family member, has been identified as the cause of microcephaly and other developmental neuroimmunopathologies in fetuses of pregnant women and Guillain‐Barre Syndrome in adults, and to date, no therapeutics or vaccines are available against ZIKV infection. In this study, we screened a limited proprietary library of diverse organic small molecules, and identified a number of leads with significant antiviral activity. Briefly, the anti‐ZIKV activity of the compounds was assayed through plaque‐forming assays in A549 cells. Subsequently, dose response assays were performed for the active compounds using the same experimental setup. Furthermore, we performed structure/activity relationship (SAR) analyses and managed to improve the anti‐ZIKV activity with the most active analogs showing activity in low picomolar range. Finally, we constructed a general model of the overall structure of these anti‐ZIKV compounds which is based on the structural similarities of all active hits. These results identify excellent template(s) with potential for further optimization of antiviral activity through rigorous SAR analyses which may be utilized for the development of inexpensive and orally available anti‐ZIKV drugs. These compounds may also be beneficial for treatment of other viruses in the same family including Dengue virus.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.