Key result
The first crystal structure of the human norovirus GII.4 protease was solved at 2.4 Å resolution, revealing structural differences from the GI.1 strain that affect inhibitor binding.
Why the study?
Drug development has focused on the norovirus GI.1 strain despite norovirus GII.4 causing over 50% of outbreaks worldwide, with no FDA-approved therapeutics available.
The first crystal structure of the norovirus GII.4 protease reveals structural differences from GI.1, enabling the design of novel inhibitors for the most clinically relevant norovirus strain.
Supports structure-based design of GII.4-specific inhibitors; hypothesis-generating pending human validation.
Norovirus is the leading cause of acute gastroenteritis worldwide with a yearly reported 700 million cases driving a $60 billion global socioeconomic burden. With no United States Food and Drug Administration approved therapeutics and the chance for severe chronic infection and life-threatening complications, researchers have identified the protease as a potential target. However, drug development has focused on the norovirus GI.1 strain despite its accounting for less than 5% of all outbreaks. Our lab aims to change focus for norovirus drug design from GI.1 to the highly infective GII.4, responsible for more than 50% of all outbreaks worldwide. With the first published crystal structure of the norovirus GII.4 protease, we have identified several significant differences in the structure and active site that have hindered development of a potent inhibitor targeting the norovirus GII.4 protease. With these new insights, we have begun designing compounds that demonstrate increased inhibition of the clinically most relevant norovirus GII.4 strain.
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Muzzarelli et al. (2019) studied Norovirus infection. Peptidomimetic protease inhibitors (Compounds A and B) vs. Norovirus GI.1 protease was evaluated on IC50 for protease inhibition. The first crystal structure of the human norovirus GII.4 protease was solved at 2.4 Å resolution, revealing structural differences from the GI.1 strain that affect inhibitor binding.
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