Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses

描述（由申请人提供）：尼帕病毒（NiV）已被认为是一种重要的生物恐怖风险和具有广泛的、不可预测的大流行潜力的全球健康风险。这种副粘病毒的感染是毁灭性的，可迅速引起致命性脑炎和严重的呼吸道感染。它通过空气或食物传播，感染机制复杂，没有药物可以预防或治疗。最近，我们成功地预防和治疗了金仓鼠的NiV感染。这一成功的关键是我们的生物分布研究的惊人发现，单次皮下注射肽产生足够的抗病毒浓度，在肺、内皮细胞，最重要的是，在大脑，NiV感染的目标器官中有效，没有任何毒性作用。我们计划利用这些信息开发高效的融合抑制抗病毒药物治疗亨尼帕病毒；确定胆固醇结合肽在中枢神经系统定位的最佳剂量方案；探讨融合抑制剂耐药机制；并在NiV疾病的动物模型中验证这些假设。我们将运用我们在化学、生物工程和病毒学方面的基础研究成果，开发一种新的广谱抗病毒策略，该策略基于系统地抑制病毒进入中枢神经系统（CNS）。通过利用这些创新的方法和技术，我们将确定开发用于人类的cns靶向融合抑制剂的可行性，并为适用于其他副粘病毒和其他急性病毒性脑碱治疗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.