Publication Date
10-14-2021
Journal
Viruses
DOI
10.3390/v13102069
PMID
34696498
PMCID
PMC8537771
PubMedCentral® Posted Date
10-14-2021
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Animals, Antiviral Agents, Binding Sites, Caliciviridae Infections, Catalytic Domain, Drug Development, Genotype, Humans, Models, Molecular, Norovirus, Peptide Hydrolases, Polyproteins, Protease Inhibitors, Protein Conformation, Protein Interaction Domains and Motifs, Viral Proteins, Virus Replication, norovirus, protease, structure, antivirals
Abstract
Human norovirus (HuNoV) infection is a global health and economic burden. Currently, there are no licensed HuNoV vaccines or antiviral drugs available. The protease encoded by the HuNoV genome plays a critical role in virus replication by cleaving the polyprotein and is an excellent target for developing small-molecule inhibitors. The current strategy for developing HuNoV protease inhibitors is by targeting the enzyme's active site and designing inhibitors that bind to the substrate-binding pockets located near the active site. However, subtle differential conformational flexibility in response to the different substrates in the polyprotein and structural differences in the active site and substrate-binding pockets across different genogroups, hamper the development of effective broad-spectrum inhibitors. A comparative analysis of the available HuNoV protease structures may provide valuable insight for identifying novel strategies for the design and development of such inhibitors. The goal of this review is to provide such analysis together with an overview of the current status of the design and development of HuNoV protease inhibitors.
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