Corilagin regulates antigen processing and presentation by directly binding to inhibit ERAP1.

Area of Science:

• Biochemistry
• Immunology
• Drug Discovery

Background:

• Endoplasmic reticulum aminopeptidase 1 (ERAP1) is crucial for MHC-I antigen processing and presentation.
• Dysregulated ERAP1 activity is linked to autoimmune diseases (MHC-I-opathy) and tumor immune evasion.

Purpose of the Study:

• To identify novel ERAP1 inhibitors.
• To investigate the therapeutic potential of identified inhibitors for MHC-I-opathy and cancer.

Main Methods:

• High-throughput screening to identify ERAP1 inhibitors.
• Biochemical assays to characterize inhibitor activity and binding mode.
• Cell-based assays using an ankylosing spondylitis model.

Main Results:

• Corilagin, a food-derived natural product, was identified as a potent and selective ERAP1 inhibitor.
• Corilagin directly binds to the ERAP1 active site competitively.
• Corilagin reversed ERAP1-induced endoplasmic reticulum stress and antigen presentation defects in a cell model.

Conclusions:

• Corilagin represents a novel therapeutic lead for MHC-I-opathy and a strategy to overcome tumor immune evasion.
• The findings provide a structural basis for designing new ERAP1 inhibitors.
• Corilagin's direct interaction with ERAP1 is a significant finding for drug development.