Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease

Acute gastroenteritis
caused by noroviruses has a major impact
on public health worldwide in terms of morbidity, mortality, and economic
burden. The disease impacts most severely immunocompromised patients,
the elderly, and children. The current lack of approved vaccines and
small-molecule therapeutics for the treatment and prophylaxis of norovirus
infections underscores the need for the development of norovirus-specific
drugs. The studies described herein entail the use of the gem-dimethyl moiety as a means of improving the pharmacological
activity and physicochemical properties of a dipeptidyl series of
transition state inhibitors of norovirus 3CL protease, an enzyme essential
for viral replication. Several compounds were found to be potent inhibitors
of the enzyme in biochemical and cell-based assays. The pharmacological
activity and cellular permeability of the inhibitors were found to
be sensitive to the location of the gem-dimethyl
group.