ERAP2

Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a protein that in humans is encoded by the ERAP2 gene. ERAP2 is part of the M1 aminopeptidase family. It is expressed along with ERAP1 in the endoplasmic reticulum (ER). In the ER, both enzymes help process and present antigens by trimming the ends of precursor peptides. This creates the optimal pieces for display by Major Histocompatibility Complex (MHC) class I molecules.

Endoplasmic reticulum aminopeptidase 2 (ERAP2) is a protein that in humans is encoded by the ERAP2 gene. ERAP2 is part of the M1 aminopeptidase family. It is expressed along with ERAP1 in the endoplasmic reticulum (ER). In the ER, both enzymes help process and present antigens by trimming the ends of precursor peptides. This creates the optimal pieces for display by Major Histocompatibility Complex (MHC) class I molecules. Although most of the phosphinic pseudopeptide analogs disclosed by Kokkala et al. in 2016 were non-selective ERAP inhibitors, compound 1 displayed nanomolar potency towards ERAP2 (IC 50 = 129 nM) with a highly improved selectivity against ERAP1, and was active in modulating the immunopeptidome of cancer cells. Hydroxamic acid triazoles In 2022, the first nanomolar selective ERAP2 inhibitors were discovered by kinetic-target guided synthesis (KTGS). A central core structure of hydroxamic acid triazoles targets the zinc ion in the catalytic site. Further investigations to optimize the activity led to nanomolar inhibitor BDM88952 (IC 50 = 3.9 nM) with the relative protein-ligand interactions studied by ERAP2 X-ray co-crystallography (Figure 1). Carboxylic acids Two hits of carboxylic acid derivatives were identified via high-throughput screening (HTS) against ERAP2, from an in-house library of 1920 compounds. Compound 3 was amongst those selected for their potency (ERAP2, IC 50 = 22 nM) and selectivity. Docking studies revealed that the carboxylic acid is predicted to coordinate the catalytic zinc ion within ERAP2. Several analogues were designed and synthesized. Sulfonamide compound 4 was identified as a potential allosteric inhibitor against ERAP2 in 2022 by Arya et al.. This compound targets ERAP2 through an uncompetitive manner (IC 50 = 44 μM) by inhibiting the hydrolysis of peptide substrates. At the same time it acts as a competitive inhibitor against ERAP1 (IC 50 = 73 μM).

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