Development of therapeutic fusion inhibitor peptides for Measles encephalitis

麻疹（MV）在世界范围内引起疾病，尽管努力通过疫苗根除，主要是因为 它很容易在人与人之间传播。MV的流行性目前阻碍了MV的根除 在发展中国家，疫苗接种率不断下降。MV疾病是 通常自限性，由于暂时性免疫， 抑制和中枢神经系统（CNS）侵袭。 MV感染后的CNS表现可在感染后早期发生，在急性 脑脊髓炎 MV诱导的CNS疾病的第二种形式是进行性感染性脑炎，称为 麻疹包涵体脑炎（MIBE），发生在免疫抑制患者1至6个月后， 麻疹感染。这是一种致命的后遗症，在不断增长的人口中很常见， 免疫功能低下的患者不能接受MV疫苗接种或对MV疫苗接种有反应。 MV引起的神经系统疾病的第三种形式-亚急性硬化性全脑炎（SSPE）- 即使在存在中和抗体的情况下，也会导致感染后数年的致命结果。数据从 最近美国的爆发显示SSPE的发病率可高达每600个受感染婴儿中有1个， 强调了这种疾病对免疫能力强的人群的重要性。 麻疹的急性或持续CNS表现没有特异性治疗。我们有 应用基础研究的结果开发了一种新的抗MV CNS感染的抗病毒策略， 基于在MV进入期间抑制膜融合。这个应用的一个主要推动力是我们发现 脂质部分与肽（称为C-肽）融合抑制剂的连接产生三个主要的 优点：（1）增加的效力;（2）跟随病毒至融合活化位点的能力;和（3） 中枢神经系统渗透。我们已经证明，我们的原型C肽可以预防致命的脑炎， 转基因小鼠模型。我们建议评估新改进的融合术的治疗效果 抑制性C肽。将使用野生型MV菌株在体外、离体和体内评估该策略 和免疫受损小鼠中的CNS适应菌株。拟议的工作将涉及两个具体问题， 目的： 1.评估C肽融合抑制剂的抗病毒疗效：体外和离体研究。 2.评价C肽融合抑制剂对MV感染的体内治疗效果 并为临床前开发提供概念验证。

Measles (MV) causes disease worldwide despite efforts towards eradication by vaccine, largely because it is spread so readily between people. MV eradication is currently hindered by the endemic nature of MV in developing countries and the decreasing rate of vaccination in developed countries. MV disease is generally self-limited with several life-threatening complications due to the temporary immune suppression and to the central nervous system (CNS) invasion. CNS manifestations following MV infection may occur early after infection, in the case of acute encephalomyelitis. A second form of MV-induced CNS disease, progressive infectious encephalitis, known as measles inclusion body encephalitis (MIBE), occurs in immunosuppressed patients 1 to 6 months after measles infection. This is a lethal sequela that is common in the growing population of immunocompromised patients, who cannot receive or respond to MV vaccination. A third form of MV-induced neurological disease – subacute sclerosing panencephalitis (SSPE) – leads to fatal outcomes years after infection even in the presence of neutralizing antibodies. Data from recent US outbreaks show that the incidence of SSPE can be as high as 1 every 600 infected infants, highlighting the significance of this disease also for the immune competent population. There is no specific therapy for acute or persistent CNS manifestations of measles. We have applied the results of fundamental research to develop a new antiviral strategy for MV CNS infection, based on inhibiting membrane fusion during MV entry. A major impetus for this application is our finding that attachment of lipid moieties to a peptide (termed C-peptide) fusion inhibitor yields three major advantages: (1) increased potency; (2) ability to follow the virus to the site of fusion activation; and (3) CNS penetration. We have shown that our prototypical C-peptide prevents lethal encephalitis in a transgenic mouse model. We propose to assess the therapeutic efficacy of newly improved fusion inhibitory C-peptides. The strategy will be assessed in vitro, ex vivo, and in vivo using wild-type strain MV and CNS adapted strains in immune-compromised mice. The proposed work will address two Specific Aims: 1. To assess the antiviral efficacy of C-peptide fusion inhibitors: in vitro and ex vivo studies. 2. To evaluate therapeutic efficacy of C-peptide fusion inhibitors against MV infection in vivo and to provide the proof of concept for pre-clinical development.