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
基本信息
- 批准号:9098588
- 负责人:
- 金额:$ 7.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:
项目摘要
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

暂无数据
数据更新时间:2024-06-01
MARLENE BOUVIER的其他基金
HLA-F in maternal-fetal immune crosstalks
HLA-F 在母胎免疫串扰中的作用
- 批准号:1066787910667879
- 财政年份:2023
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Immune evasion by SARS-CoV-2: the role of HLA class I
SARS-CoV-2 的免疫逃避:HLA I 类的作用
- 批准号:1057529210575292
- 财政年份:2022
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Understanding ERAP molecular mechanism of MHC I antigen processing
了解 MHC I 抗原加工的 ERAP 分子机制
- 批准号:1018088110180881
- 财政年份:2017
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Understanding ERAP molecular mechanism of MHC I antigen processing
了解 MHC I 抗原加工的 ERAP 分子机制
- 批准号:93834159383415
- 财政年份:2017
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Subversion of MHC class I antigen presentation by viral immunomodulatory proteins
病毒免疫调节蛋白颠覆 MHC I 类抗原呈递
- 批准号:89967078996707
- 财政年份:2014
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Subversion of MHC class I antigen presentation by viral immunomodulatory proteins
病毒免疫调节蛋白颠覆 MHC I 类抗原呈递
- 批准号:92064129206412
- 财政年份:2014
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Subversion of MHC class I antigen presentation by viral immunomodulatory proteins
病毒免疫调节蛋白颠覆 MHC I 类抗原呈递
- 批准号:87236058723605
- 财政年份:2014
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Molecular mechanism of immune evasion by the E3-19K protein of Adenovirus
腺病毒E3-19K蛋白免疫逃避的分子机制
- 批准号:85324478532447
- 财政年份:2012
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Molecular mechanism of virus-mediated immune evasion
病毒介导的免疫逃避的分子机制
- 批准号:72840147284014
- 财政年份:2006
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Molecular mechanism of virus-mediated immune evasion
病毒介导的免疫逃避的分子机制
- 批准号:75591307559130
- 财政年份:2006
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
相似国自然基金
用于急性出血控制的硅酸钙复合海绵的构建及其促凝血性能和机制研究
- 批准号:32301097
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
AF9通过ARRB2-MRGPRB2介导肠固有肥大细胞活化促进重症急性胰腺炎发生MOF的研究
- 批准号:82300739
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
代谢工程化MSC胞外囊泡靶向调控巨噬细胞线粒体动力学改善急性肾损伤的作用及机制研究
- 批准号:32371426
- 批准年份:2023
- 资助金额:50 万元
- 项目类别:面上项目
DUSP2介导自噬调控气管上皮细胞炎症在急性肺损伤中的机制研究
- 批准号:82360379
- 批准年份:2023
- 资助金额:32 万元
- 项目类别:地区科学基金项目
超声射频信号神经回路策略模型定量肌肉脂肪化评估慢加急性肝衰竭预后
- 批准号:82302221
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Treatment Development for Smoking Cessation and Engagement in HIV/TB Care in South Africa
南非戒烟和参与艾滋病毒/结核病护理的治疗方法开发
- 批准号:1070687410706874
- 财政年份:2023
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
An mHealth implementation strategy to address the syndemic of mental illness, hypertension, and HIV in Uganda
解决乌干达精神疾病、高血压和艾滋病毒综合症的移动医疗实施战略
- 批准号:1075299210752992
- 财政年份:2023
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Universal Rapid test for HIV Diagnosis
HIV 诊断的通用快速检测
- 批准号:1076141510761415
- 财政年份:2023
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
m6A mRNA reader proteins in the AIDS-opportunistic pathogen Toxoplasma gondii
艾滋病机会致病菌弓形虫中的 m6A mRNA 阅读器蛋白
- 批准号:1061537410615374
- 财政年份:2023
- 资助金额:$ 7.58万$ 7.58万
- 项目类别:
Host cell membrane perforation during invasion by Toxoplasma gondii
弓形虫入侵过程中宿主细胞膜穿孔
- 批准号:1058765810587658
- 财政年份:2023
- 资助金额:$ 7.58万$ 7.58万
- 项目类别: