Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses

摘要 尼帕（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， 无法预测的大流行的可能性。这种副粘病毒的感染是毁灭性的， 脑炎和严重呼吸道感染。通过空气或食物传播，其感染机制是 目前还没有药物可以预防或治疗它。最近，我们已经成功地预防和治疗了NiV。 金黄仓鼠的感染这一成功的关键是我们的生物分布研究中令人惊讶的发现， 肽的单次皮下注射产生足够的抗病毒浓度， 肺，内皮，最重要的是，在大脑中，NiV感染靶向的器官，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， henipaviruses;以确定最佳剂量方案的中枢神经系统定位胆固醇结合的 肽;研究融合抑制剂的耐药机制;并测试这些假设， NiV病的动物模型。我们将应用我们在化学方面的基础研究成果， 生物工程和病毒学的发展，一个新的广谱抗病毒策略的基础上，抑制 病毒进入全身以及中枢神经系统（CNS）。利用这些创新 方法和技术，我们将确定开发CNS靶向融合抑制剂的可行性， 人类使用，也为适用于其他副粘病毒的平台技术和 治疗其他急性病毒性脑炎。 1

Abstract 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 biodistribution 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. 1