Design of CNS-targeted peptide entry inhibitors for emerging henipaviruses

摘要 Nipah(Niv)已被认为是一种重要的生物恐怖风险和全球健康风险， 不可预测的大流行可能性。这种副粘病毒的感染是毁灭性的，迅速导致致命 脑炎和严重的呼吸道感染。通过空气或食物传播，其感染机制是 复杂，并且没有药物可以预防或治疗它。最近，我们成功地预防和治疗了新城疫 感染金黄仓鼠。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 单次皮下注射该多肽可产生足够的抗病毒浓度，有效治疗 肺、内皮，最重要的是，在大脑中，被新城疫病毒感染的器官，没有任何 有毒的影响。我们计划利用这些信息开发高效的融合抑制抗病毒药物 确定胆固醇结合的中枢神经系统定位的最佳剂量方案 多肽；研究对融合抑制剂的抗性机制；并在 新城疫的动物模型。我们将把我们的基础研究成果应用于化学领域， 生物工程和病毒学开发基于抑制作用的广谱抗病毒新策略 病毒进入全身以及中枢神经系统(CNS)。通过利用这些创新的 方法和技术，我们将确定开发针对中枢神经系统的融合抑制剂的可行性 人类使用，也为平台技术适用于其他副粘液病毒和 其他急性病毒性脑炎的治疗。 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