| Summary: | ERAP1 has been associated with a set of immune-mediated diseases, including ankylosing spondylitis. Currently, there is no selective and potent ERAP1 inhibitor available that would allow in-depth research of its functions and roles in diseases. Therefore, the aim of this work is to apply fragment-based drug design approach for the development of such inhibitor. A set of 12 structurally diverse hits was identified as a result of a screen containing 1200+ fragments using orthogonal ERAP1 activity assays. These hits can be used as a basis for development of a larger lead inhibitor, which requires structural information about their binding mode to ERAP1. Three different approaches have been tried in order to obtain such information about the binding mode. Unfortunately, ERAP1 crystallisation trials did not succeed, the potential reason being heterogeneity of the protein samples due to presence of several glycoforms. A set of 31 analogues of an IRAP inhibitor, which has been shown to inhibit ERAP1 activity, was synthesised and screened providing valuable structure-activity relationship information. Taken together, the screening campaign has resulted in a novel ERAP1 inhibitor with a single digit micromolar potency against ERAP1.
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