Oxadiazole-Based Cell Permeable Macrocyclic Transition State Inhibitors of Norovirus 3CL Protease

Human
noroviruses are the primary causative agents of acute gastroenteritis
and a pressing public health burden worldwide. There are currently
no vaccines or small molecule therapeutics available for the treatment
or prophylaxis of norovirus infections. Norovirus 3CL protease plays
a vital role in viral replication by generating structural and nonstructural
proteins via the cleavage of the viral polyprotein. Thus, molecules
that inhibit the viral protease may have potential therapeutic value.
We describe herein the structure-based design, synthesis, and in vitro and cell-based evaluation of the first class of oxadiazole-based,
permeable macrocyclic inhibitors of norovirus 3CL protease.