Small molecule probes of ERAP-1

描述(申请人提供)：这个项目旨在发现ERAP1的小分子化学探针，ERAP1是一种与免疫系统中的抗原呈递有关的氨基肽酶。ERAP1基因多态性最近被认为与自身免疫性疾病有关，包括强直性脊柱炎和牛皮癣。已知ERAP1在某些多肽被加载到I类MHC蛋白之前为它们提供最终的修剪步骤，但这些多肽的身份及其在自身免疫性疾病发展中的作用尚不清楚。这项工作的长期目标是了解ERAP1的S在免疫系统健康和疾病中的作用，并开发缓解自身免疫病理的治疗方法。这项研究的具体目标是与美国国立卫生研究院分子文库探测中心网络(MPLCN)合作实施验证的高通量筛选，以确定ERAP1的小分子抑制剂(目标1)，采用先前验证的二次分析来验证已确定的HITS的生物学相关性(目标2)，以及与MLPCN合作，使用先前验证的第三次分析(目标3)来开发和表征化学探针(S)。

DESCRIPTION (provided by applicant): 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).