Small molecule inhibitors of adenovirus-induced downregulation of MHC I

腺病毒诱导的 MHC I 下调的小分子抑制剂

• 批准号: 9098588
• 负责人: MARLENE BOUVIER
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9098588
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Address; Adenovirus E3 19K Protein; Adenovirus Infections; Adenoviruses; Adult; Antigen Presentation; Antiviral Agents; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Assay; Biotechnology; CD8B1 gene; Cell Culture Techniques; Cell surface; Cells; Child; Cidofovir; Clinical; Collaborations; Complex; Computer Assisted; Cytolysis; Cytotoxic T-Lymphocytes; Data; Disease; Down-Regulation; Endoplasmic Reticulum; Fluorescence; Future; Ganciclovir; Generations; Goals; HLA-A2 Antigen; Health; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens Class I; Human; I-antigen; Immune; Immunocompromised Host; Individual; Infection; Knowledge; Lead; Libraries; Life; Link; Mediating; Molecular; Monitor; Morbidity - disease rate; Mutate; Organ Transplantation; Patients; Pharmacologic Substance; Play; Population; Proteins; Research; Respiratory System; Respiratory tract structure; Ribavirin; Role; Serotyping; Solid; Specificity; Staging; Structure; T cell response; Testing; Time; Toxic effect; Transplant Recipients; Validation; Viral; Viral Antigens; Virus; Work; base; drug development; experience; gastrointestinal; high throughput screening; immune function; improved; inhibitor/antagonist; innovation; mortality; novel therapeutics; professor; respiratory; response; screening; small molecule; small molecule inhibitor; small molecule libraries; viral detection; Acquired Immunodeficiency Syndrome; Acute; Address; Adenovirus E3 19K Protein; Adenovirus Infections; Adenoviruses; Adult; Antigen Presentation; Antiviral Agents; Binding; Binding Proteins; Binding Sites; Biochemical; Biological Assay; Biotechnology; CD8B1 gene; Cell Culture Techniques; Cell surface; Cells; Child; Cidofovir; Clinical; Collaborations; Complex; Computer Assisted; Cytolysis; Cytotoxic T-Lymphocytes; Data; Disease; Down-Regulation; Endoplasmic Reticulum; Fluorescence; Future; Ganciclovir; Generations; Goals; HLA-A2 Antigen; Health; Hematopoietic Stem Cell Transplantation; Histocompatibility Antigens Class I; Human; I-antigen; Immune; Immunocompromised Host; Individual; Infection; Knowledge; Lead; Libraries; Life; Link; Mediating; Molecular; Monitor; Morbidity - disease rate; Mutate; Organ Transplantation; Patients; Pharmacologic Substance; Play; Population; Proteins; Research; Respiratory System; Respiratory tract structure; Ribavirin; Role; Serotyping; Solid; Specificity; Staging; Structure; T cell response; Testing; Time; Toxic effect; Transplant Recipients; Validation; Viral; Viral Antigens; Virus; Work; base; drug development; experience; gastrointestinal; high throughput screening; immune function; improved; inhibitor/antagonist; innovation; mortality; novel therapeutics; professor; respiratory; response; screening; small molecule; small molecule inhibitor; small molecule libraries; viral detection

 DESCRIPTION (provided by applicant): Adenoviruses (Ads) are widespread in the human population and cause infections linked to a number of illnesses of the gastrointestinal and respiratory tracks. Although acute Ad infection is rarely fatal in healthy adults, it is a significnt cause of morbidity and mortality in children and immunocompromised adults such as hematopoietic stem cell transplant recipients and AIDS patients. The antiviral drugs cidofovir, ribavirin, and ganciclovir commonly used to treat Ad infections are toxic and ineffective in most patients. Several studies have shown that control of Ad infection in patients is associated with the detection of virus-specific cytotoxic T- lymphocyte (CTL) responses. In a significant number of acutely infected individuals, these responses are however insufficient to control the virus and consequently viral persistence develops. Ad persistence is linked to its E3-19K protein that binds to and retains MHC class I molecules in the endoplasmic reticulum (ER) of infected cells. E3-19K suppresses the presentation of viral antigens by MHC I molecules, making Ad-infected cells less sensitive to lysis by CTLs. The goal of this application is to evaluate the E3-19K/MHC I complex as a target for the identification of small molecule inhibitors. We hypothesize that small molecule inhibitors of the E3-19K/MHC I interaction will restore normal antigen presentation by MHC I on infected cells, and sensitize the infected cells to lysis by CTLs. We have studied the molecular mechanism of immune evasion evolved by E3-19K for more than 10 years. Recently, we determined the x-ray structure of Ad serotype 2 (Ad2) E3-19K bound to HLA-A2. Our findings provide a rationale to test the hypothesis that the E3-19K/MHC I interaction can be disrupted by small molecules. The Specific Aims are: (1) To develop a new biochemical assay to identify small molecule inhibitors of the Ad2 E3-19K/HLA-A2 interaction. This assay will be optimized through initial high throughput screening of small molecule libraries; and (2) To apply a structure-based computational screening approach in which the Ad2 E3-19K/HLA-A2 interface is probed for its potential to be targeted by small molecules. The significance of our studies is highlighted by the clinical threat that Ad infection presents to immunocompromised individuals as well as the current lack of formally approved treatments against Ad. The idea of inhibiting the E3-19K-induced suppression of MHC I antigen presentation with a small molecule is highly innovative. This research is expected to set the stage for more extensive screening of large chemical libraries and validation tests in future studies.

 描述（由适用提供）：腺病毒（AD）在人群中宽度宽度，并引起与胃肠道和呼吸道疾病多种疾病有关的感染。尽管急性AD感染在健康的成年人中很少致命，但这是儿童和免疫功能低下的成年人（例如造血干细胞移植者）和艾滋病患者的发病率和死亡率的重要原因。在大多数患者中，通常用于治疗AD感染的抗病毒药物Cidofovir，Ibavirin和Ganciclovir通常用于治疗AD感染。几项研究表明，对患者的AD感染的控制与检测病毒特异性细胞毒性T-淋巴细胞（CTL）反应有关。但是，在大量急性感染的个体中，这些反应不足以控制病毒，因此病毒持久性发展。 AD持久性与其E3-19K蛋白有关，该蛋白与感染细胞的内质网（ER）结合并保留了MHC I类分子。 E3-19K抑制了MHC I分子对病毒抗原的表现，从而使AD感染的细胞对CTL的裂解敏感。该应用的目的是评估E3-19K/MHC I复合物作为鉴定小分子抑制剂的目标。我们假设E3-19K/MHC I相互作用的小分子抑制剂将恢复MHC I对感染细胞的正常抗原表现，并将感染细胞敏感到CTL裂解。我们研究了E3-19K进化的免疫进化的分子机制超过10年。最近，我们确定了与HLA-A2结合的AD血清型2（AD2）E3-19K的X射线结构。我们的发现提供了一个基本原理，以检验以下假设：E3-19K/MHC I相互作用可能会被小分子破坏。具体目的是：（1）开发一种新的生化测定，以鉴定AD2 E3-19K/HLA-A2相互作用的小分子抑制剂。该测定将通过对小分子库的初始高通量筛选进行优化； （2）采用基于结构的计算筛选方法，其中对AD2 E3-19K/HLA-A2界面进行了探测，其潜力是小分子的靶向。 AD感染对免疫功能低下的个体以及目前缺乏针对AD的正式批准的治疗方法的临床威胁，强调了我们研究的重要性。用小分子抑制E3-19K诱导的MHC I抗原表现的抑制的想法是高度创新的。预计这项研究将为更广泛的大型化学图书馆和未来研究中的验证测试奠定基础。