Inhibitors of proprotein convertases

Area of Science:

• Biochemistry
• Enzymology
• Molecular Biology

Background:

• Mammalian subtilases, also known as proprotein convertases (PCs) or subtilisin-like proprotein convertases (SPCs), were discovered in 1990.
• Seven PCs cleave at basic amino acid residues, while two subtypes (SKI-1/S1P and NARC-1/PCSK9) cleave at nonbasic residues.
• PCs play significant roles in various physiological processes and diseases, including tumorigenesis, diabetes, viral infections, and neurodegenerative disorders.

Purpose of the Study:

• To explore the therapeutic potential of modulating proprotein convertase (PC) activity.
• To review the development of PC inhibitors for disease intervention and enzyme characterization.
• To identify lead structures for developing more potent and specific nonpeptide PC inhibitors.

Main Methods:

• Review of literature on proprotein convertase (PC) discovery and functional roles.
• Analysis of various inhibitor strategies, including bioengineered serpin proteins, peptide inhibitors, and nonpeptide compounds.
• Evaluation of the therapeutic implications of PC activity modulation in diverse pathologies.

Main Results:

• Numerous studies highlight the involvement of PCs in health and diseases such as cancer, diabetes, and Alzheimer's disease.
• Bioengineered serpin proteins, like alpha1-PDX, and peptide inhibitors have shown success in modulating PC activity.
• Nonpeptide inhibitors, including diterpenes and metal ion ligands, exhibit modest inhibition but serve as valuable lead structures.

Conclusions:

• Proprotein convertases (PCs) are critical targets for therapeutic intervention due to their roles in numerous diseases.
• The development of PC inhibitors, particularly nonpeptide-based ones, holds significant promise for future drug discovery.
• Further research into PC inhibitors could lead to novel treatments for a wide range of human pathologies.