Antiviral Drug Discovery: Norovirus Proteases and Development of Inhibitors

Abstract

Proteases are a major enzyme group playing important roles in a wide variety of biological processes in life forms ranging from viruses to mammalians. The aberrant activity of proteases can lead to various diseases; consequently, host proteases have been the focus of intense investigation as potential therapeutic targets. A wide range of viruses encode proteases which play an essential role in viral replication and, therefore, constitute attractive targets for the development of antiviral therapeutics. There are numerous examples of successful drug development targeting cellular and viral proteases, including antivirals against human immunodeficiency virus and hepatitis C virus. Most FDA-approved antiviral agents are peptidomimetics and macrocyclic compounds that interact with the active site of a targeted protease. Norovirus proteases are cysteine proteases that contain a chymotrypsin-like fold in their 3D structures. This review focuses on our group’s efforts related to the development of norovirus protease inhibitors as potential anti-norovirus therapeutics. These protease inhibitors are rationally designed transition-state inhibitors encompassing dipeptidyl, tripeptidyl and macrocyclic compounds. Highly effective inhibitors validated in X-ray co-crystallization, enzyme and cell-based assays, as well as an animal model, were generated by launching an optimization campaign utilizing the initial hit compounds. A prodrug approach was also explored to improve the pharmacokinetics (PK) of the identified inhibitors.

Potential Inhibitor of COVID-19 Main Protease (M^pro) From Several Medicinal Plant Compounds by Molecular Docking Study

“…The disruption of protease activity can lead to various diseases; thus, commonly, host proteases can be used as potential therapeutic targets. In many viruses, proteases play essential roles in viral replication; therefore, proteases are often used as protein targets during the development of antiviral therapeutics [22].…”

Comparative Docking Analysis of Rational Drugs Against COVID-19 Main Protease

“…The disruption of protease activity can cause various diseases; thus, commonly, host proteases are often used as potential therapeutic targets. In many viruses, proteases play essential roles in viral replication; therefore, proteases are often used as protein targets during the event of antiviral therapeutics (17).…”

Viral replicons as valuable tools for drug discovery

“…The HCV genome encodes a polyprotein that is proteolytically cleaved by the viral NS3/4A and cellular proteases into the three structural proteins: Core, Envelope protein 1 and Envelope protein 2, and the seven nonstructural proteins: p7, NS2, NS3, NS4A, NS4B, NS5A and NS5B. Most HCV strains will not establish productive infection in cell culture and it was not until 2005 that JFH-1 was shown to be the first strain that could be HCV replicon [19] DENV genome DENV replicon [40] DENV replicon [45] CHIKV genome CHIKV replicon [61] CHIKV replicon [61] SINV replicon [60] RSV genome RSV minigenome [76] RSV replicon [78] NV genome NV replicon [93] EBOV genome EBOV minigenome [98] Structural proteins…”

“…The Groutas lab at Witchita State University rationally designs protease inhibitors of norovirus and other viruses, and tests compounds using replicon systems (reviewed in Ref. [93]). Four nucleoside analogues were tested on the norovirus replicon, with 2 0 -C-methylcytidine showing good antiviral activity [94].…”