Small molecule probes of ERAP-1

ERAP-1小分子探针

• 批准号: 8446272
• 负责人: Lawrence J. Stern
• 金额: $ 4.11万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-20 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446272
• 关键词: Active Sites; Adipocytes; Affinity; Amino Acids; Aminopeptidase; Ankylosing spondylitis; Antigen Presentation; Antigens; Arthritis; Arts; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biological; Biological Assay; Cellular Assay; Characteristics; Chemicals; Coumarins; Databases; Development; Disease; Disease Association; Endoplasmic Reticulum; Enzymes; Excision; Family; Fluorogenic Substrate; Genbank; Genetic Polymorphism; Health; Hydrolysis; Immune system; Length; Leucine; Leucine Aminopeptidase; Libraries; Ligand Binding; Ligands; Link; Literature; Major Histocompatibility Complex; Methods; Modeling; Molecular Bank; Molecular Conformation; Morphologic artifacts; N-terminal; Online Mendelian Inheritance In Man; Pathology; Peptides; Persons; Predisposition; Process; Proteins; Psoriasis; Puromycin; Regulation; Reporting; Research; Role; Specificity; Structure; Structure-Activity Relationship; SwissProt; Testing; Therapeutic; Time; Tumor Necrosis Factor-alpha; Ubenimex; United States National Institutes of Health; Variant; Work; alpha benzopyrone; antigen processing; base; counterscreen; design; genome wide association study; high throughput screening; inhibitor/antagonist; receptor; screening; small molecule; therapy development

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).

描述（由申请人提供）：本项目旨在发现ERAP 1的小分子化学探针，ERAP 1是一种参与免疫系统抗原呈递的氨肽酶。最近，ERAP 1多态性与强直性脊柱炎和银屑病等自身免疫性疾病有关。已知ERAP 1在某些肽被加载到I类MHC蛋白之前为它们提供最终的修剪步骤，但是这些肽的身份及其在自身免疫性疾病发展中的作用尚不清楚。这项工作的广泛的长期目标是了解ERAP 1在免疫系统健康和疾病中的作用，并开发减轻自身免疫病理学的治疗方法。该研究的具体目标是与NIH分子库探针中心网络（MPLCN）合作，实施经验证的高通量筛选以鉴定ERAP 1的小分子抑制剂（目标1），采用先前验证的二级测定来验证鉴定的命中的生物学相关性（目标2），并与MLPCN合作，使用先前验证的三级测定法开发和表征化学探针（目的3）。