Structure-guided design, synthesis, x-ray crystallography, and biochemical and in vivo evaluation of novel series of viral 3cl protease inhibitors of norovirus (NV) and Middle East Respiratory Distress Syndrome coronavirus (MERS-CoV)
Galasiti Kankanamalage, Anushka Chathuranga
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Norovirus infection constitutes the primary cause of acute viral gastroenteritis. There are currently no vaccines or norovirus-specific antiviral therapeutics available for the management of norovirus infection. Norovirus 3C-like protease is essential for viral replication, consequently, inhibition of this enzyme is a fruitful avenue of investigation that may lead to the emergence of anti-norovirus therapeutics. This dissertation describes the structure-based discovery and optimization of a novel series of dipeptidyl inhibitors of norovirus 3C-like protease using X-ray crystallography, iterative structure-activity relationship (SAR) studies, enzyme and cell-based replicon system studies, as well as efficacy studies using small and large animal models. In addition, based on the hypothesis that the S4 subsite of the protease may provide an effective means of designing potent and cell permeable inhibitors, a structure-guided approach was used to identify lead compounds and validate the aforementioned hypothesis. A lead compound identified during the course of these studies was shown to have efficacy in the murine model of norovirus infection. Furthermore, multiple series of novel prodrugs (ester and carbamate) of transition state latent inhibitors and transition state mimics with optimal pharmacological activity and pharmacokinetics were designed, synthesized and evaluated. A series of norovirus 3CL protease inhibitors that embody an ?-ketophosphonate warhead is also reported for the first time. Finally, a serendipitous discovery resulted in the identification of a feline infection peritonitis virus (FIPV) inhibitor shown in clinical trials to be effective in the treatment of FIP.
Thesis (Ph.D.)-- Wichita State University, College of Liberal Arts and Sciences, Dept. of Chemistry