Drug design for flavivirus proteases: what are we missing?

Area of Science:

• Virology
• Drug Discovery
• Biochemistry

Background:

• Limited progress in developing drug candidates for Dengue virus (DENV) and West Nile virus (WNV) proteases.
• Contrast with Hepatitis C virus (HCV) NS3/NS4A protease, which has approved peptidomimetic drugs.
• Flavivirus proteases are targets for antiviral therapies.

Purpose of the Study:

• Compare DENV and WNV NS3 proteases with HCV NS3/NS4A protease.
• Investigate reasons for slow progress in flavivirus protease inhibitor development.
• Determine if flavivirus proteases are inherently more challenging drug targets.

Main Methods:

• Comparative analysis of flavivirus (DENV, WNV) and HCV NS3 protease structures and functions.
• Review of high-throughput screening campaigns and identified peptidic inhibitors.
• Assessment of research investment in neglected flavivirus disease targets.

Main Results:

• Identified peptidic inhibitors for DENV and WNV proteases exist.
• High-throughput screening campaigns have been conducted.
• Progress towards clinical drug candidates has been notably slow.

Conclusions:

• The slow progress may be due to limited resources invested in these neglected targets rather than inherent protease challenges.
• Further research and investment are crucial for advancing DENV and WNV protease inhibitors.
• Understanding protease complexities is key for developing effective antiviral treatments.