Targeting eukaryotic proteases for natural products-based drug development.

Area of Science:

• Biochemistry and Pharmacology
• Drug Discovery and Development

Background:

• Proteases regulate physiological processes; their dysregulation is linked to diseases like cancer, diabetes, and viral infections.
• Natural products are a historically validated source for therapeutic agents, inspiring over half of marketed drugs.
• Over 60% of marketed protease inhibitors are derived from or mimic natural products.

Purpose of the Study:

• To review current and emerging protease drug targets and their disease relevance.
• To highlight successful FDA-approved protease inhibitors with natural product scaffolds.
• To discuss recent pharmacologically characterized inhibitors from marine and terrestrial sources.

Main Methods:

• Literature review of protease inhibitors up to April 2020.
• Analysis of natural product scaffolds in approved drugs.
• Examination of structure-based design advancements.
• Review of biological assessments linking inhibitors to disease states.

Main Results:

• Natural products are a rich source for potent and selective protease inhibitors.
• Structure-based design has accelerated the development of optimized lead compounds.
• Numerous successful protease inhibitors are derived from or inspired by natural product structures.
• Significant progress has been made in identifying and characterizing novel natural inhibitors.

Conclusions:

• Protease inhibitors derived from natural products represent a critical therapeutic strategy.
• Continued exploration of natural sources and structure-based design will yield new treatments for various diseases.
• Natural product-based protease inhibitors offer a validated pathway for drug development.