Discovery of Selective Inhibitors of Endoplasmic Reticulum Aminopeptidase 1

Area of Science:

• Biochemistry
• Immunology
• Drug Discovery

Background:

• Endoplasmic reticulum-resident zinc aminopeptidase ERAP1 is crucial for immune function, trimming peptides for MHC loading.
• ERAP1's paralogs, ERAP2 and IRAP, share structural similarities, making selective inhibition challenging.

Purpose of the Study:

• To discover and characterize the first selective inhibitors of ERAP1.
• To explore the potential of these inhibitors as therapeutic agents for ERAP1-related conditions.

Main Methods:

• Synthesis and characterization of novel small molecules targeting ERAP1.
• Biochemical assays to determine enzyme kinetics and inhibition mechanisms (competitive, allosteric).
• Cellular assays to assess the impact of inhibitors on antigen presentation.

Main Results:

• Compounds 1 and 2 are identified as competitive ERAP1 inhibitors.
• Compound 3 exhibits both allosteric activation and competitive inhibition depending on the substrate.
• Compounds 2 and 3 demonstrate inhibition of antigen presentation in cellular assays.
• Compound 3 shows increased potency against an ERAP1 variant linked to autoimmune disease risk.

Conclusions:

• Novel selective ERAP1 inhibitors have been discovered, providing valuable tools for research.
• These inhibitors offer mechanistic insights into ERAP1 specificity and function.
• Targeted ERAP1 inhibition presents a promising therapeutic avenue for immune and autoimmune diseases.