Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses

描述（由申请人提供）：尼帕病毒（NiV）已被公认为是一种重要的生物恐怖风险和全球健康风险，具有广泛的、不可预测的大流行潜力。这种副粘病毒的感染是毁灭性的，迅速引起致命的脑炎和严重的呼吸道感染。NiV通过空气或食物传播，感染机制复杂，目前尚无药物防治，近年来，我们成功地防治了金黄地鼠NiV感染。这一成功的关键是来自我们的生物分布研究的令人惊讶的发现，即肽的单次皮下注射产生足够的抗病毒浓度，以在肺，内皮，最重要的是，在大脑中，NiV感染靶向的器官中有效，而没有任何毒性作用。我们计划利用这些信息来开发高效的融合抑制抗病毒药物的henipaviruses，以确定最佳的剂量方案的中枢神经系统定位胆固醇结合肽，研究耐融合抑制剂的机制，并测试这些假设在动物模型的NiV疾病。我们将应用我们在化学，生物工程和病毒学的基础研究的结果，以抑制病毒进入系统以及在中枢神经系统（CNS）的基础上开发一种新的广谱抗病毒策略。通过利用这些创新方法和技术，我们将确定开发CNS靶向融合抑制剂用于人类的可行性，并为适用于其他副粘病毒和治疗其他急性病毒性脑炎的平台技术奠定基础。

DESCRIPTION (provided by applicant): Nipah (NiV) has been recognized as both an important bioterror risk and a global health risk with broad, unpredictable pandemic potential. Infection from this paramyxovirus is devastating, rapidly causing lethal encephalitis and serious respiratory infections. Transmitted by air or food, its mechanism of infection is complex, and no drugs exist to prevent or treat it. Recently, we have successfully prevented and treated NiV infection in golden hamsters. Key to this success is the surprising finding from our biodistributio studies, that a single subcutaneous injection of the peptide generates sufficient antiviral concentrations for effectiveness in the lung, endothelium and, most importantly, in the brain, the organs targeted by NiV infection, without any toxic effect. We plan to use this information to develop highly effective fusion-inhibitory antivirals for henipaviruses; to determine the optimal dose regimens for CNS localization of cholesterol-conjugated peptides; to investigate the mechanisms of resistance to fusion inhibitors; and to test these hypotheses in animal models of NiV disease. We will apply the results of our fundamental research in chemistry, bioengineering and virology to the development of a new broad-spectrum antiviral strategy based on inhibiting virus entry systemically as well as in the central nervous system (CNS). By utilizing these innovative approaches and technologies, we will determine the feasibility of developing CNS-targeted fusion inhibitors for human use, and also set the stage for a platform technology applicable to other paramyxoviruses and for the treatment of other acute viral encephalitides.