Structure-based design and optimization of dipeptidyl inhibitors of norovirus 3CL protease

Abstract

Noroviruses are the primary cause of acute gastroenteritis. They are associated with increased hospitalization and mortality among the elderly and immunocompromised patients. In developing countries, noroviruses are linked to significant mortality (200,000) in children < 5 years old. Importantly, norovirus infection poses a high bioterrorism threat, and the problem is further compounded by the current dearth of effective vaccines or norovirus-specific antivirals. The studies described in this thesis lay the groundwork for the discovery and development of small molecule therapeutics for the treatment and prophylaxis of norovirus infection. Specifically, these studies have as their primary focus the structurebased design and optimization of a dipeptidyl series of inhibitors of norovirus 3CL protease, an enzyme shown to be essential for replication of the virus and a validated target for the development of anti-norovirus therapeutics. The studies described herein include the synthesis and in vitro biochemical evaluation of dipeptidyl transition state inhibitors and transition state mimics of 3CL protease. The selectivity of the inhibitors, as well as the anti-norovirus activity of the synthesized compounds in a cell-based replicon system was also evaluated..