Hit to Lead Optimization of Non-Peptidic Inhibitors of Alphaviral Cysteine Protease

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Project Summary Emerging viral infections caused by mosquito-borne alphaviruses such as Venezuelan/West- ern/Eastern equine encephalitis virus (VEEV, EEEV or WEEV) and Chikungunya virus are loom- ing threats to public health systems around the world. There are no vaccines or therapeutics ap- proved for human use against alphaviruses, and we have limited understanding of the molecular pathogenicity of most alphaviruses. If regional or transnational outbreak of alphavirus infections occur in the future, loss of life and loss of economic productivity can be minimized or prevented if therapeutic or prophylactic agents are available. In this application, we propose an investiga- tion into a new series of molecules that inhibit the protease domain of the non-structural protein 2 (nsP2) of VEEV, blocks the replication of VEEV in human cells, and are amenable to systematic structural changes that is important for drug development. The main goals of this project are: (a). To investigate covalent and mechanism-based reversible inhibitors of nsP2 using multiparameter structure-activity studies relationships (SAR) studies along with complementary metabolic and bioavailability studies; and (b). To investigate the molecular interactions between the molecules and nsP2 using crystallography and molecular modelling, which will facilitate target-specific op- timization of drug lead candidates. The project goals will facilitate the advancement of the com- pound series towards preclinical investigation as first-in-class nsP2 inhibitors that have anti-al- phaviral activities at physiologically relevant concentrations. Additionally, the molecules will also serve as valuable molecular tools to advance our understanding of the role of nsP2 in the pathogenicity of alphaviruses.