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: 10414909
• 负责人: Matteo Porotto
• 金额: $ 35.44万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414909
• 关键词: Acute; Address; Animal Model; Antiviral Agents; Binding; Biodistribution; Brain; C-Peptide; C-terminal; Cell membrane; Cell surface; Cells; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Central Nervous System Diseases; Central Nervous System Infections; Cessation of life; Child; Child Mortality; Chimeric Proteins; Cholesterol; Chronic; Complication; Data; Developed Countries; Developing Countries; Disadvantaged; Disease; Disease Outbreaks; Encephalitis; Encephalomyelitis; Evaluation; Evolution; Fatal Outcome; General Population; Glycoproteins; HIV; Hemagglutinin; Herd Immunity; Home; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Immunosuppression; Impairment; In Vitro; Incidence; Individual; Infant; Infection; Infectious Encephalitis; Investigation; Lead; Life; Lipids; Lung; Measles; Measles virus; Mediating; Membrane Fusion; Modeling; Mus; N-terminal; National Institute of Allergy and Infectious Disease; Nature; Neuraxis; Neurons; Paramyxovirus; Penetration; Peptides; Periodicity; Persons; Play; Population; Pregnant Women; Process; Publishing; Research; Risk; Role; SLAM protein; Site; Subacute Sclerosing Panencephalitis; Tissues; Toxic effect; Transgenic Mice; Treatment Efficacy; United States; Vaccinated; Vaccination; Vaccinee; Vaccines; Viral; Virus; Virus Diseases; Work; anti-viral efficacy; attenuated measles virus; base; drug discovery; experience; fundamental research; immunogenicity; improved; in vitro testing; in vivo; in vivo evaluation; infant infection; inhibitor; lead candidate; lead optimization; mouse model; nectin; neglect; neutralizing antibody; preclinical development; pressure; prevent; prophylactic; receptor; therapeutic development; unvaccinated; viral resistance; virus envelope; virus-induced neurologic disease

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.

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。拟议的工作将解决两个具体问题 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。

项目成果

Nebulized fusion inhibitory peptide protects cynomolgus macaques from measles virus infection.

雾化融合抑制肽可保护食蟹猴免受麻疹病毒感染。

• DOI: 10.21203/rs.3.rs-1700877/v1
• 发表时间: 2022
• 期刊: Research square
• 作者: Reynard,Olivier;Gonzalez,Claudia;Dumont,Claire;Iampietro,Mathieu;Ferren,Marion;LeGuellec,Sandrine;Laurie,Lajoie;Mathieu,Cyrille;Carpentier,Gabrielle;Roseau,Georges;Bovier,FrancescaT;Zhu,Yun;LePennec,Deborah;Montharu,Jérome;A
• 通讯作者: A

Self-assembly Stability Compromises the Efficacy of Tryptophan-Containing Designed Anti-measles Virus Peptides

自组装稳定性损害了含色氨酸设计的抗麻疹病毒肽的功效

• 发表时间: 2019
• 期刊: Journal of Nanomedicine & Nanotechnology
• 作者: E. Martínez

Repurposing an In Vitro Measles Virus Dissemination Assay for Screening of Antiviral Compounds.

• DOI: 10.3390/v14061186
• 发表时间: 2022-05-29
• 期刊: Viruses

Inhibition of Measles Viral Fusion Is Enhanced by Targeting Multiple Domains of the Fusion Protein.

• DOI: 10.1021/acsnano.1c02057
• 发表时间: 2021-08-24
• 期刊: ACS nano
• 影响因子: 17.1
• 作者: Bovier FT;Rybkina K;Biswas S;Harder O;Marcink TC;Niewiesk S;Moscona A;Alabi CA;Porotto M
• 通讯作者: Porotto M

Rapid and Flexible Platform To Assess Anti-SARS-CoV-2 Antibody Neutralization and Spike Protein-Specific Antivirals.

• DOI: 10.1128/msphere.00571-21
• 发表时间: 2021-08-25
• 期刊: mSphere
• 影响因子: 4.8
• 作者: Stelitano D;Weisberg SP;Goldklang MP;Zhu Y;Bovier FT;Kalantarov GF;Greco G;Decimo D;Franci G;Cennamo M;Portella G;Galdiero M;Mathieu C;Horvat B;Trakht IN;Moscona A;Whitt MA;Porotto M
• 通讯作者: Porotto M