This project is directed at discovery of small-molecule chemical probes for ERAP1, an aminopeptidase involved in antigen presentation in the immune system. ERAP1 polymorphisms recently have been linked to autoimmune diseases including ankylosing spondylitis and psoriasis. ERAP1 is known to provide the final trimming steps for certain peptides before they are loaded onto class I MHC proteins, but the identity of these peptides and their role in development of autoimmune disease is not known. The broad long-term objective of this work is to understand ERAP1's role in immune system health and disease, and to develop therapeutic approaches to alleviation of autoimmune pathology.
The specific aims of the research are to collaborate with the NIH Molecular Libraries Probe Center Network (MPLCN) to implement a validated high-throughput screen to identify small molecule inhibitors of ERAP1 (aim 1), to employ previously validated secondary assays to validate the biological relevance of identified hits (aim 2), and to colaborate with MLPCN to develop and characterize chemical probe(s) using a previously validated tertiary assay (aim 3).
In this project we will use high-throughput screening methods to identify a chemical probe for ERAP1, an enzyme involved in the process by which the immune system recognizes foreign material in the body. Recently, person-to-person variation in ERAP1 has been linked with susceptibility to autoimmune diseases like arthritis and psoriasis, but the mechanism is not known. Development of a chemical probe for ERAP1 will facilitate discovery of the mechanism of disease association and potentially will guide efforts to develop therapies for these diseases.