Targeting the Regulatory Site of ER Aminopeptidase 1 Leads to the Discovery of a Natural Product Modulator of Antigen Presentation

ER
aminopeptidase 1 (ERAP1) is an intracellular enzyme that generates
antigenic peptides and is an emerging target for cancer immunotherapy
and the control of autoimmunity. ERAP1 inhibitors described previously
target the active site and are limited in selectivity, minimizing
their clinical potential. To address this, we targeted the regulatory
site of ERAP1 using a high-throughput screen and discovered a small
molecule hit that is highly selective for ERAP1. (4aR,5S,6R,8S,8aR)-5-(2-(Furan-3-yl)­ethyl)-8-hydroxy-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic
acid is a natural product found in Dodonaea viscosa that constitutes a submicromolar, highly selective, and cell-active
modulator of ERAP1. Although the compound activates hydrolysis of
small model substrates, it is a competitive inhibitor for physiologically
relevant longer peptides. Crystallographic analysis confirmed that
the compound targets the regulatory site of the enzyme that normally
binds the C-terminus of the peptide substrate. Our findings constitute
a novel starting point for the development of selective ERAP1 modulators
that have potential for further clinical development.