Peroxidasin Inhibition by Phloroglucinol and Other Peroxidase Inhibitors

Area of Science:

• Biochemistry
• Enzymology
• Pharmacology

Background:

• Human peroxidasin (PXDN) is a widely expressed enzyme implicated in various pathologies, including cardiovascular disease, cancer, and fibrosis.
• PXDN generates reactive species, contributing to oxidative damage in biological systems.
• Inhibiting PXDN activity presents a potential therapeutic strategy for related diseases.

Purpose of the Study:

• To investigate the inhibitory effects of phloroglucinol and other compounds on human peroxidasin (PXDN) activity.
• To identify potent and specific PXDN inhibitors for therapeutic development.
• To characterize the mechanism of inhibition for promising compounds.

Main Methods:

• Screening of 15 peroxidase inhibitors against PXDN.
• Enzyme kinetics assays using sequential stopped-flow spectrophotometry.
• Assessment of inhibitory activity in decellularized extracellular matrix and cell culture models.

Main Results:

• Phloroglucinol demonstrated potent inhibition of PXDN, with nanomolar IC50 values for purified enzyme.
• Phloroglucinol effectively inhibited HOBr-mediated collagen IV cross-linking in complex biological models.
• Phloroglucinol was identified as an irreversible PXDN inhibitor, suggesting mechanism-based or tight-binding interactions.

Conclusions:

• Phloroglucinol is a highly promising lead compound for designing specific PXDN inhibitors.
• The developed assays are suitable for high-throughput screening of PXDN inhibitors.
• Targeting PXDN with inhibitors like phloroglucinol offers a potential therapeutic avenue for diseases associated with its activity.