posted on 2020-03-09, 17:34authored byJohn Liddle, Jonathan P. Hutchinson, Semra Kitchen, Paul Rowland, Margarete Neu, Ted Cecconie, Duncan S. Holmes, Emma Jones, Justyna Korczynska, Despoina Koumantou, Jonathan D. Lea, Leng Nickels, Michelle Pemberton, Alex Phillipou, Jessica L. Schneck, Hester Sheehan, Christopher P. Tinworth, Iain Uings, Justyna Wojno-Picon, Robert J. Young, Efstratios Stratikos
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.