Design, synthesis, and biochemical evaluation of novel inhibitors of Norwalk virus 3CL protease
Mandadapu, Sivakoteswara Rao
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Noroviruses are the most common cause of acute gastroenteritis in the US and worldwide, accounting for ~21 million cases of gastroenteritis annually in the US alone. Noroviruses are very stable in the environment and refractory to many common disinfectants, with only a few viral particles required to initiate virus infection. Therefore, norovirus outbreaks are hard to contain using routine sanitation, and even implementation of aggressive sanitary measures often fails to prevent subsequent norovirus outbreaks. Norovirus infection is a serious public health problem and underscores the importance of developing small molecule anti-norovirus therapeutics and prophylactics. However, there are currently no approved drugs or vaccines available for the treatment of norovirus infection. Norovirus 3CL protease is a druggable target that is well-suited to the discovery and development of anti-norovirus therapeutics and prophylactics. This dissertation describes the design, synthesis, and biochemical evaluation of the first series of inhibitors of norovirus 3CL protease. The identified hits were optimized using structure-based drug design approaches, to generate lead compounds with high pharmacological activity, selectivity, and drug-like characteristics.
Thesis (Ph.D.)-- Wichita State University, Fairmount College of Liberal Arts and Sciences, Dept. of Chemistry