ROLE OF CELL INTEGRINS IN ADENOVIRAL CONJUNCTIVITIS

细胞整合素在腺病毒结膜炎中的作用

基本信息

批准号：
8134293
负责人：
Glen R Nemerow
金额：
$ 45.58万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-01-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8134293
关键词：
Acute respiratory infection Adenovirus Infections Adenoviruses Affinity Antiviral Agents Basic Science Binding Binding Sites Biochemical Capsid Capsid Proteins Cells Cellular Structures Chimera organism Clinical Research Complex Conjunctivitis Cryoelectron Microscopy Defensins Development Disease Epidemic Keratoconjunctivitis Eye Eye Infections Frequencies Funding Gastrointestinal tract structure Goals HDAC5 gene Human Adenovirus Infections Human Adenoviruses Human Papillomavirus Immune Immune system Immunocompromised Host In Vitro Infection Integrins Investigation Knowledge Lead Libraries Lysosomes Medical Molecular Morbidity - disease rate Pathway interactions Peptides Play Property Proteins Resistance Role Site Structure Surface Plasmon Resonance Therapeutic Time Viral Virion Virus Visual Acuity X ray diffraction analysis X-Ray Diffraction adenovirus penton protein antimicrobial peptide base combinatorial effective therapy high throughput screening human neutrophil peptide 1 improved insight late endosome microbial multidisciplinary novel pathogen prevent public health relevance small molecule small molecule libraries stoichiometry three dimensional structure

项目摘要

DESCRIPTION (provided by applicant): Human adenoviruses are major causes of acute infections of the respiratory, gastrointestinal tract, and the eye. In severe cases of ocular infections, such as those occurring in epidemic keratoconjunctivitis, adenovirus can cause significant morbidity and loss of visual acuity. At the present time, there are few if any effective antiviral agents that have been approved for the treatment of adenovirus eye infections. The studies proposed here seek to remedy this situation by capitalizing on the significant progress made during the previous funding period as well as our new preliminary studies. Specifically, we propose to undertake a systematic and multidisciplinary investigation of the antiviral activities of naturally occurring antimicrobial peptides (AMPs) and novel synthetic small molecules. The major goal of the proposed studies is to determine precisely how AMPs and synthetic small molecules intervene in the adenovirus cell entry pathway. This goal will be achieved by: 1) identifying the adenoviral coat proteins that are recognized by AMPs and synthetic molecules; 2) analyzing the precise adenovirus binding properties of AMPs; 3) solving the three-dimensional structure of adenovirus-AMP complexes by X-ray diffraction and cryoelectron microscopy; and 4) employing high-throughput screens of combinatorial libraries to discover novel synthetic small molecules that restrict adenovirus infection. These investigations should not only improve our knowledge of adenovirus structure and the mechanisms involved in host cell entry but could also lead to the development of new treatments for adenovirus-induced ocular diseases. PUBLIC HEALTH RELEVANCE: Human adenoviruses infections are generally self-limiting, however fatal disseminated adenovirus infections are appearing with increasing frequency in immunocompromised patients. Moreover, effective treatments for adenovirus ocular infections remain an unmet medical need. The studies proposed here seek to improve the prospects of developing better antiviral therapeutics by analyzing the inhibitory activities of naturally occurring antimicrobial peptides as well as new synthetic small molecules. )

描述（由申请人提供）：人类腺病毒是呼吸道、胃肠道和眼睛急性感染的主要原因。在严重的眼部感染病例中，例如流行性角结膜炎，腺病毒可导致严重的发病率和视力丧失。目前，被批准用于治疗腺病毒眼部感染的有效抗病毒药物很少。这里提出的研究旨在通过利用上一个资助期间取得的重大进展以及我们新的初步研究来纠正这种情况。具体来说，我们建议对天然存在的抗菌肽（AMP）和新型合成小分子的抗病毒活性进行系统和多学科的研究。拟议研究的主要目标是精确确定 AMP 和合成小分子如何干预腺病毒细胞进入途径。这一目标将通过以下方式实现：1）鉴定被 AMP 和合成分子识别的腺病毒外壳蛋白； 2）分析AMP精确的腺病毒结合特性； 3）通过X射线衍射和冷冻电镜解析腺病毒-AMP复合物的三维结构； 4) 采用组合文库的高通量筛选来发现限制腺病毒感染的新型合成小分子。这些研究不仅可以提高我们对腺病毒结构和宿主细胞进入机制的了解，还可以开发出针对腺病毒引起的眼部疾病的新疗法。公共卫生相关性：人类腺病毒感染通常具有自限性，但致命的播散性腺病毒感染在免疫功能低下的患者中出现的频率越来越高。此外，腺病毒眼部感染的有效治疗仍然是未满足的医疗需求。这里提出的研究旨在通过分析天然存在的抗菌肽以及新的合成小分子的抑制活性来改善开发更好的抗病毒疗法的前景。）