Noroviruses are the most common cause of acute gastroenteritis, accounting for over 23 million cases annually in the U.S. alone. Norovirus infections constitute an important health problem for which there are no specific antiviral therapeutics or vaccines. In this thesis, (a) structure-activity relationship studies were carried out using the acyclic sulfamide scaffold. Several derivatives based on this scaffold were found to inhibit norovirus in a cell-based replicon system and, (b) a series of bisulfite adducts derived from representative transition state inhibitors (dipeptidyl aldehydes and ?-ketomides) was synthesized and shown to exhibit anti-norovirus activity in a cell-based replicon system. The ED50 of the most effective inhibitor was 60 nM. This study demonstrates for the first time the utilization of bisulfite adducts of transition inhibitors in the inhibition of norovirus 3CL protease in vitro and in a cell-based replicon system. The approach described herein can be extended to the synthesis of the bisulfite adducts of other classes of transition state inhibitors of serine and cysteine proteases, such as ?-ketoheterocycles and ?-ketoesters. Taken together, this thesis describes the discovery of two novel classes of inhibitors of noroviruses.