Development of therapeutic fusion inhibitor peptides for Measles encephalitis

开发治疗麻疹脑炎的融合抑制肽

• 批准号: 8095381
• 负责人: Matteo Porotto
• 金额: $ 23.01万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8095381
• 关键词: Acute; Amino Acid Substitution; Animal Model; Antiviral Agents; Binding; Biological Availability; Blood - brain barrier anatomy; Cell membrane; Central Nervous System Diseases; Central Nervous System Infections; Cessation of life; Chikungunya virus; Child; Chimeric Proteins; Cholesterol; Communicable Diseases; Complement; Complex; Critiques; Development; Disease; Dominant-Negative Mutation; Effectiveness; Encephalitis; Encephalomyelitis; Entropy; Evaluation; F Protein Measles Virus; HIV; Hendra Virus; Human; Immunocompromised Host; In Vitro; Individual; Infection; Infectious Encephalitis; Kinetics; Lead; Measles; Measles virus; Mediating; Membrane; Membrane Fusion; Modeling; Mus; Neuraxis; New Agents; Para-Influenza Virus Type 3; Paramyxovirus; Penetration; Peptides; Population; Protein Region; Proteins; SLAM protein; Series; Site; Structure; Study Section; Subacute Sclerosing Panencephalitis; Testing; Therapeutic; Transgenic Mice; Transgenic Organisms; Transmembrane Domain; Update; Vaccination; Vaccines; Viral; Viral Encephalitis; Viral Fusion Proteins; Virus; West Nile virus; Writing; base; enthalpy; fundamental research; human trophoblast leucocyte common antigen; in vivo; inhibitor/antagonist; meetings; mouse model; pathogen; pre-clinical; prevent; protein aminoacid sequence; receptor; research study; therapeutic development

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.

描述（由申请人提供）：随着最近出现的一系列严重中枢神经系统感染的新病原体，包括几种引起人类致命脑炎的人畜共患病毒，病毒性脑炎正在引起警惕。一种长期以来一直是人类病原体的病毒仍然排在榜首：麻疹。麻疹病毒（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。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能发生在感染后早期，如急性脑脊髓炎，或在感染后数年，由于亚急性硬化性全脑炎的病毒持续存在。麻疹病毒引起的第三种中枢神经系统疾病是进行性感染性脑炎，发生在麻疹感染后1至6个月，并且在免疫功能低下的患者中越来越成问题。目前尚无针对麻疹急性或持续性中枢神经系统并发症的特异性治疗方法。我们建议将我们的基础研究成果应用于麻疹中枢神经系统感染的新抗病毒策略的开发。这一建议是基于我们最近的发现，将胆固醇基团附着在肽融合抑制剂上产生3个主要优势：(1)增强效力，(2)肽与病毒在融合激活位点定位，(3)穿透中枢神经系统。我们发现胆固醇标记肽在体外对麻疹病毒非常有效，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其治疗麻疹感染中枢神经系统的潜力。通过序列优化与胆固醇标记相结合的方法，我们建议开发高效的肽融合抗病毒药物，在体外抑制中压脑炎，并在相关的中压脑炎动物模型上测试其治疗潜力。我们将通过：Aim 1进行我们的主要候选治疗药物的临床前开发。靶向质膜的MV融合抑制剂肽的先导优化，使用(a)生物物理分析引导的序列优化，和(b)膜靶向。目标2。融合抑制剂对野生型MV诱导的麻疹脑炎的保护作用。我们将评估(a)目标肽的生物利用度，以及(b)在CD150（SLAM）转基因小鼠模型的攻毒实验中的有效性。因此，我们将获得有效性的原理证明，使我们能够选择具有最大体内潜力的肽进行进展。