ROLE OF CELL INTEGRINS IN ADENOVIRAL CONJUNCTIVITIS

描述（由申请方提供）：人腺病毒是呼吸道、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，如流行性角膜结膜炎中发生的那些，腺病毒可导致显著的发病率和视力丧失。目前，几乎没有任何有效的抗病毒剂已被批准用于治疗腺病毒眼部感染。本报告所建议的研究，旨在利用上一个资助期内取得的重大进展，以及我们新进行的初步研究，纠正这种情况。具体而言，我们建议进行系统的和多学科的调查，天然存在的抗菌肽（AMP）和新的合成小分子的抗病毒活性。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AMP和合成分子识别的腺病毒外壳蛋白; 2）分析AMP的精确腺病毒结合特性; 3）通过X射线衍射和冷冻电子显微镜解决腺病毒-AMP复合物的三维结构;和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的合成小分子。这些研究不仅可以提高我们对腺病毒结构和进入宿主细胞的机制的认识，而且还可能导致腺病毒诱导的眼部疾病的新治疗方法的发展。 公共卫生相关性：人腺病毒感染通常是自限性的，然而，在免疫功能低下的患者中，致命的播散性腺病毒感染的频率越来越高。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。本文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治疗剂的前景。)

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. )