Erap1

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that in humans is encoded by the ERAP1 gene. This M1 zinc aminopeptidase is involved in the antigen processing and presentation pathway. ERAP1 is mainly located in the endoplasmic reticulum (ER), where it trims peptides at their N-terminus, adapting them for presentation by MHC class I molecules (MHC-I).

Endoplasmic reticulum aminopeptidase 1 (ERAP1) is an enzyme that in humans is encoded by the ERAP1 gene. This M1 zinc aminopeptidase is involved in the antigen processing and presentation pathway. ERAP1 is mainly located in the endoplasmic reticulum (ER), where it trims peptides at their N-terminus, adapting them for presentation by MHC class I molecules (MHC-I). The ERAP1 gene (HGNC: 18173) is located at the long arm of chromosome 5 (5q15). The gene is ~47Kb in length and contains 20 exons and 19 introns, which encode 9 different splice variants. The coding sequence shows a high degree of conservation among placental mammals (>80% identity). The sequences of 227 ERAP1 orthologs identified in approximately 200 species are available. The first generation of ERAP1 inhibitors is a series of phosphinic pseudopeptides derived from a rational design approach targeting the catalytic zinc-binding site, in 2013 1 . Notably, DG013A (Table 1, Figure 3) displayed high potency (ERAP1 IC 50 = 33 nM) but poor selectivity against ERAP2 and IRAP, with reported SAR optimization studies demonstrating the importance of side chains at positions P 1 ' and P 2 '. A high-resolution crystal structure of phosphinic analogue DG046 bound in the active site of ERAP1, has been obtained (Figure 4). DABA analogues A novel family of zinc-targeting diaminobenzoic acid (DABA) compounds were rationally designed and developed in 2013, displaying micromolar potency for ERAP1 inhibition (compound 2, IC 50 = 2 μM, Table 1). Moderate selectivity over ERAP2 and IRAP with additional optimization efforts based on extensive investigation of SAR has been achieved. Urea derivatives In 2020, urea derivative 3 (Table 1) was identified via high-throughput screening (HTS), as a competitive inhibitor of ERAP1 aminopeptidase activity (IC 50 = 6.9 μM) with increased selectivity over ERAP2 and IRAP. SAR exploration and docking studies showed that the N-acetylpiperazine carbonyl group was critical for the activity via its zinc-binding group properties. Optimization of a library screening hit has led to the identification of cyclohexyl acids with excellent potency (pIC50 = 8.6), cellular activity (pIC50 = 7.7) and moderate unbound clearance and oral bioavailability highlighting the promise of this series as drug leads. Clerodane acid A high-throughput library screen identified Clerodane acid, a natural product from Dodonaea viscosa, to be a selective activator of ERAP1 for small substrates and an inhibitor of peptide trimming. This compound was found active in blocking ERAP1-dependent antigen presentation (EC50 = 1μΜ) and to bind to the regulatory site of ERAP1 that normally accommodates C-termini of peptide substates. Clerodane acid was also found to induce strong immunopeptidome shifts in cancer cells. Benzofurans This family of compounds were identified as potential allosteric (C-terminus recognition site of peptides) inhibitor via fluorescence-based high-throughput screening in 2021. Compound 4 (Table 1) displayed high potency (ERAP1 IC 50 = 34 nM) and at the same time selectivity against ERAP2 and IRAP. Sulfonamides Sulfonamide compound 5 (Table 1) was identified through high-throughput screening studies as a potential allosteric selective inhibitor, binding at the interface between domain II and IV of ERAP1. It activates small peptide hydrolysis but effectively inhibits processing of long peptides with 8−13 residues (IC 50 = 5.3 μM) and displays selectivity over ERAP2 and IRAP.

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