Development of therapeutic fusion inhibitor peptides for Measles encephalitis

描述(申请人提供)：病毒性脑炎正在上升，这是一个令人担忧的原因，最近出现了一系列严重的中枢神经系统感染的新病原体，包括几种可导致人类致命脑炎的人畜共患病毒。一种长期以来一直是人类病原体的病毒仍然位居榜首：麻疹。尽管努力通过疫苗根除麻疹病毒(MV)，但它在世界范围内仍会导致疾病，这主要是因为它很容易在人与人之间传播。虽然这种疾病通常是自限性的，但一些严重的并发症涉及中枢神经系统，并导致后遗症或死亡。这些中枢神经系统表现可在感染后早期出现，如急性脑脊髓炎，或感染数年后，由于亚急性硬化性全脑炎病毒持续存在。MV引起的第三种中枢神经系统疾病是进行性传染性脑炎，发生在麻疹感染后1至6个月，在日益增长的免疫功能低下患者中是有问题的。麻疹的急性或持续性中枢神经系统并发症尚无特效治疗方法。我们建议将我们的基础研究成果应用于开发针对麻疹中枢神经系统感染的新的抗病毒策略。这一建议是基于我们最近的发现，即将胆固醇基团连接到多肽融合抑制剂上产生3个主要优点：(1)增强效力，(2)多肽与融合激活部位的病毒定位，(3)中枢神经系统穿透。我们发现胆固醇标记的多肽在体外对麻疹病毒具有高效的抗病毒作用，我们建议在表达MV受体人CD150(SLAM)的转基因小鼠脑炎模型中评估它们治疗麻疹中枢神经系统感染的潜力。通过将序列优化和胆固醇标记相结合，我们建议开发在体外抑制MV的高效肽融合抗病毒药物，并在相关的MV脑炎动物模型中测试它们的治疗潜力。我们将通过以下方式开展我们的先导治疗候选药物的临床前开发：目的1.利用(A)生物物理分析引导的序列优化和(B)膜靶向，对靶向质膜的MV融合抑制物肽进行先导优化。目的2.在转基因小鼠模型中，融合抑制物对野生型MV诱导的麻疹脑炎的保护作用。我们将评估(A)靶向多肽的生物利用度，以及(B)在CD150(SLAM)转基因小鼠模型中的攻击实验中的有效性。因此，我们将获得有效性的原则证据，使我们能够选择具有最大体内潜力的多肽进行进展。 与公共卫生相关：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(CNS)感染的新病原体，包括西尼罗河病毒、基孔肯雅病毒和其他人畜共患病病毒，这些病毒会导致人类发生致命性脑炎。一种长期以来一直是人类病原体的病毒仍然位居榜首：麻疹。目前还没有针对麻疹引起的重要中枢神经系统疾病的特效药。我们最近的几项进展，包括发现了一种开发有效的副粘病毒融合抑制剂并将这些分子运送到血脑屏障的方法，现在已经准备好应用于中枢神经系统的麻疹疾病。这些策略值得迫切寻求，以开发针对麻疹的靶向抗病毒化合物。 免责声明：请注意，以下批评是由评审员在研究小组会议之前准备的，基本上是以未经编辑的形式提供的。虽然审查员有机会根据小组的讨论更新或修订其书面评价，但不能保证在会议讨论之后更新了个别批评意见。因此，这些评论可能不能完全反映个别评审员在小组讨论结束时的最终意见或小组的最终多数意见。因此，讨论纪要和总结是审查员在会议上实际上认为至关重要的最后结论。

DESCRIPTION (provided by applicant): Viral encephalitis is rising as a cause for alarm, with the recent emergence of a series of new agents of serious CNS infection, including several zoonotic viruses that cause lethal encephalitis in humans. One virus that has long been a human pathogen remains at the top of the list: measles. Measles virus (MV) causes disease worldwide despite efforts towards eradication by vaccine, largely because it is spread so readily between people. While the disease is generally self-limited, several serious complications involve the CNS and lead to sequelae or death. These CNS manifestations may occur early after infection, in the case of acute encephalomyelitis, or years after infection, as a result of viral persistence in subacute sclerosing panencephalitis. The third form of MV-induced CNS disease, progressive infectious encephalitis, occurs 1 to 6 months following measles infection, and is problematic in an increasing population of immunocompromised patients. There is no specific therapy for acute or persistent CNS complications of measles. We propose to apply the results of our fundamental research to the development of a new antiviral strategy for measles CNS infection. The proposal is based on our recent discovery that attachment of a cholesterol group to a peptide fusion inhibitor yields 3 major advantages: (1) increased potency, (2) localization of the peptide with the virus at the site of fusion activation, and (3) CNS penetration. We showed that cholesterol- tagged peptides are highly effective against measles virus in vitro, and we propose to assess their potential to treat measles infection of the CNS in a transgenic murine encephalitis model expressing the MV receptor human CD150 (SLAM). By combining sequence optimization with cholesterol tagging, we propose to develop highly effective peptide fusion antivirals that inhibit MV in vitro, and to test their therapeutic potential in a relevant animal model of MV encephalitis. We will pursue preclinical development of our lead therapeutic candidate by: Aim 1. Lead optimization of MV fusion inhibitor peptides targeted to the plasma membrane, using (a) biophysical analysis-guided sequence optimization, and (b) membrane targeting. Aim 2. Effectiveness of the fusion inhibitors to protect from measles encephalitis induced by wild type MV in a transgenic murine model. We will assess (a) bioavailability of the targeted peptides, and (b) efficacy in challenge experiments in a CD150(SLAM) transgenic mouse model. We will thereby obtain proof of principle for efficacy, allowing us to select peptides for advancement that have the most in vivo potential. PUBLIC HEALTH RELEVANCE: Viral encephalitis is rising as a cause for alarm, with the recent emergence of a series of new agents of serious central nervous system (CNS) infection, including West Nile virus, Chikungunya virus, and other zoonotic viruses that cause lethal encephalitis in humans. One virus that has long been a human pathogen remains at the top of the list: measles. Currently there is no specific treatment for the important CNS disease caused by measles. Several of our recent advances, including discovery of a way to develop effective paramyxovirus fusion inhibitors and to deliver these molecules across the blood brain barrier, are now ready to be applied to measles diseases of the CNS. These strategies are worth urgently pursuing to develop targeted antiviral compounds for measles. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of the individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.