Recent Advances in Targeting Viral Proteases for the Discovery of Novel Antivirals

Abstract

The occurrence of life-threatening viral infections and the establishment of appropriate defense strategies exhibit major challenges to the disease management in our society. The unpredictable character of viral outbreaks will even be enhanced in the future due to human activities such as increasing international travel, deforestation, changes in social conditions, or influences induced by the climate change. The defense against these pathogenic agents requires preparedness, including successful drug design strategies. Viral proteases represent attractive targets for the design of anti-infective lead compounds, as in case that a viral mRNA encoding several types of proteins is recognized as a monocistronic template by the host-cell translation machinery, the presence of protease activities is required for processing the viral polyprotein precursor into structural or non-structural components essential for the formation of new virion particles. In addition, viral proteases can be involved in further processes relevant for viral replication. Numerous efforts have been made to develop potent small-molecule inhibitors of viral proteases, however, until now only a limited number reached the market. In the present contribution, functional aspects of the target proteases, their structural properties, drug design strategies, resulting inhibitors, and resistance management are reviewed and discussed by means of the four essential representative cases of HIV, HCV, SARS coronavirus, and the flaviviruses Dengue and West Nile virus.

A Phenotypic Assay to Identify Chikungunya Virus Inhibitors Targeting the Nonstructural Protein nsP2

“…More recently, protease inhibitors have been developed with success against HIV and hepatitis C virus and are developed against other viruses. 36 However, both polymerase and protease inhibitors target enzymatic activities carried by viral proteins. In the near future, a new class of antiviral molecules should emerge that will aim at blocking interactions between viral and cellular components.…”

Important Advances in the Field of Anti-Dengue Virus Research

“…This viral-encoded enzyme also functions as a helicase, presenting a second modality that could be targeted. Protease inhibitors have already been developed against other flaviviruses, such as HCV [89], reviewed in [90,91]. Work with in silico docking programmes has led to the identification of potential inhibitors of DENV NS3 protein, two of which were shown to have activity in cell culture models [92,93].…”

Structural analysis of peptides that fill sites near the active center of the two different enzyme molecules by artificial intelligence and computer simulations

“…Functional characterization of proteases is beneficial for curing many diseases, [1][2][3] and should promote their industrial use in sectors such as food production and cosmetics. 4 The function of proteases is largely characterized by the peptide binding mechanism, and it is desirable to identify peptides that are suitable binders near the active center of proteases.…”