Other proline-specific proteases

Other proline-specific proteases (PSPs) represent a diverse group of enzymes, distinct from dipeptidyl peptidase 4 (DPP4), that are specialized in cleaving peptide bonds involving proline residues, which are typically resistant to general proteolysis (ACS, 2023; NIH, 2022). This category includes enzymes such as dipeptidyl peptidase 8 (DPP8), dipeptidyl peptidase 9 (DPP9), fibroblast activation protein (FAP), and prolyl oligopeptidase (POP), which play vital roles in the processing of peptide hormones, neuropeptides, and chemokines (ResearchGate, 2025). In the pharmaceutical industry, these enzymes are primarily recognized as critical off-targets for DPP4 inhibitors (gliptins) used in treating type 2 diabetes; high selectivity for DPP4 over these 'other' proteases is required to prevent severe toxicities, such as multiorgan failure and immune dysfunction linked to DPP8/9 inhibition (NIH, 2009; ResearchGate, 2010). However, certain members like FAP are actively pursued as primary therapeutic targets in oncology due to their high expression in the tumor microenvironment and role in stromal remodeling (BAS, 2014). Additionally, POP is investigated for its potential role in neurodegenerative disorders like Alzheimer's disease (ACS, 2023). This target entry is considered 'incorrect' as a single molecule because it refers to a collective functional class of enzymes rather than a specific protein entity.

Other names

Post-proline cleaving enzymesPPCEsProlyl peptidasesProline-specific peptidasesS9 family proteases

Inhibition of the catalytic activity of enzymes that cleave peptide bonds adjacent to proline residues, thereby modulating the half-life and activity of bioactive peptides such as GLP-1, substance P, and neuropeptide Y.