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

 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(申请人提供)：腺病毒(ADS)广泛存在于人群中，可引起与多种胃肠道和呼吸道疾病有关的感染。虽然急性Ad感染在健康成人中很少致死，但它是儿童和免疫功能低下的成年人(如造血干细胞移植受者和艾滋病患者)发病率和死亡率的重要原因。通常用于治疗Ad感染的抗病毒药物西多福韦、利巴韦林和更昔洛韦对大多数患者有毒且无效。一些研究表明，控制患者的Ad感染与检测病毒特异性细胞毒性T淋巴细胞(CTL)反应有关。然而，在相当数量的急性感染患者中，这些反应不足以控制病毒，从而形成病毒持久性。AD的持久性与其E3-19K蛋白有关，该蛋白结合并保留感染细胞的内质网(ER)中的MHC I类分子。E3-19K抑制MHC I类分子呈递病毒抗原，使Ad感染的细胞对CTL的裂解不那么敏感。本应用的目的是评价E3-19K/MHC I复合体作为鉴定小分子抑制剂的靶标。我们推测，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提呈，并使感染细胞对CTL的裂解敏感。我们对E3-19K免疫逃逸的分子机制进行了10多年的研究。最近，我们确定了与人类白细胞抗原A2结合的腺病毒血清型2(AD2)E3-19K的X射线结构。我们的发现为检验E3-19K/MHC I相互作用可以被小分子破坏的假设提供了理论基础。其具体目的是：(1)建立一种新的生化分析方法来鉴定AD2 E3-19K/HLA-A2相互作用的小分子抑制剂。本实验将通过小分子文库的初步高通量筛选进行优化； (2)应用基于结构的计算筛选方法，探索AD2 E3-19K/HLA-A2界面作为小分子靶向的可能性。Ad感染对免疫受损个体的临床威胁，以及目前缺乏正式批准的治疗方法，突显了我们研究的意义。用小分子抑制E3-19K诱导的MHC I抗原提呈抑制的想法具有很高的创新性。这项研究有望为未来研究中更广泛地筛选大型化学库和验证测试奠定基础。