Design of selective protein-inhibitors for human peroxidases

Heme peroxidases are vital enzymes in the human body, each with specialized roles. Peroxidasin stabilizes the extracellular matrix, while thyroid peroxidase is essential for producing thyroid hormones. Other heme peroxidases, such as myeloperoxidase (MPO), eosinophil peroxidase (EPO), and lactoperoxidase, are crucial for the innate immune system, helping to neutralize pathogens in blood and mucosal fluids by producing highly reactive substances. However, these substances can also damage the bodys own tissues, leading to inflammation. Chronic inflammation, such as in atherosclerosis, can have severe health consequences. To address this, the pharmaceutical industry is developing drugs to block these enzymes and prevent inflammation. However, designing such drugs is challenging because heme peroxidases share structural similarities, and off- target effects on related enzymes could cause serious side effects. Highly specific inhibitors are therefore needed, requiring a detailed understanding of the structural differences between these enzymes. Interestingly, the human pathogen Staphylococcus aureus has evolved a natural solution to this problem. It produces a small protein called SPIN, which specifically binds to and inhibits MPO. SPIN uses a two-part mechanism: a globular domain binds to MPOs surface, while a short peptide inserts into its active site, blocking its activity. This precise interaction allows S. aureus to neutralize MPO without affecting other enzymes, offering a model for designing selective inhibitors. This project investigates the structural, kinetic, and thermodynamic properties of SPIN and its interaction with MPO. Using molecular modeling and X-ray crystallography, researchers aim to understand these interactions at the atomic level and compare MPO and EPO to identify exploitable structural differences. These insights will guide the development of new, highly specific drugs to block harmful peroxidase activity while preserving their beneficial functions. The results of this project will pave the way for future laboratory and clinical studies.