Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses

描述(由申请人提供)：Nipah(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，迅速导致致命性脑炎和严重的呼吸道感染。通过空气或食物传播，其感染机制复杂，目前还没有预防或治疗的药物。最近，我们成功地预防和治疗了金黄地鼠的新城疫病毒感染。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，即单次皮下注射这种多肽就能产生足够的抗病毒浓度，对肺、内皮，最重要的是对新城疫病毒感染所针对的器官--大脑--有效，而且没有任何毒性作用。我们计划利用这些信息开发针对Heipav病毒的高效融合抑制抗病毒药物；确定胆固醇结合多肽的CNS定位的最佳剂量方案；研究融合抑制剂的抗性机制；并在Niv病的动物模型中测试这些假说。我们将应用我们在化学、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，其基础是从系统和中枢神经系统(CNS)抑制病毒入侵。通过利用这些创新的方法和技术，我们将确定开发人类使用的CNS靶向融合抑制剂的可行性，并为适用于其他副粘病毒和治疗其他急性病毒性脑炎的平台技术奠定基础。 公共卫生意义：病毒性脑炎日益引起人们的警觉，最近出现了一系列严重中枢神经系统感染的新病原体，包括西尼罗河病毒、基孔肯雅病毒和其他可导致人类致死性脑炎的人畜共患病毒。副粘病毒导致重要的人类疾病，这些疾病对全球疾病和死亡率有很大贡献。作为这项提议的主题的人畜共患副粘病毒尼帕病毒，由于其致命性脑炎和可传播的性质，是公共卫生的紧急关切。目前提出的抗病毒药物可能有效地减少病毒复制，但无法治疗脑内感染，因为它们不能自由扩散通过血脑屏障(BBB)。因此，开发能够穿透血脑屏障的抗病毒药物是一个关键的未得到满足的医学需求。我们提出了一种策略，通过血脑屏障传递一种抗病毒药物，以阻止中枢神经系统的病毒感染。

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. PUBLIC HEALTH RELEVANCE: Viral encephalitis is rising as a cause for alarm, with the recent emergence of a series of new agents of serious CNS infection, including West Nile virus, Chikungunya virus, and other zoonotic viruses that cause lethal encephalitis in humans. Paramyxoviruses cause important human illnesses that contribute significantly to global disease and mortality. The zoonotic paramyxovirus that is the subject of this proposal, Nipah virus, is an urgent concern for public health due to its lethal encephalitis and transmissible nature. Current proposed antiviral drugs, which may be effective in reducing viral replication, cannot treat infection in the brain because they cannot freely diffuse across the blood-brain barrier (BBB). The development of antivirals which can penetrate the BBB is therefore a critical unmet medical need. We propose a strategy to deliver an antiviral drug across the BBB to block viral infection in the CNS.