Development of therapeutic fusion inhibitor peptides for Measles encephalitis

开发治疗麻疹脑炎的融合抑制肽

基本信息

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
项目类别：
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

项目摘要

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.

尽管努力通过疫苗根除麻疹（MV），但它仍然在世界范围内引起疾病，主要原因是 MV 的流行性目前阻碍了它在人与人之间传播。发展中国家的疫苗接种率正在下降，而发达国家的疫苗接种率正在下降。由于临时免疫系统的影响，通常具有自限性，并伴有多种危及生命的并发症抑制和中枢神经系统（CNS）侵袭。 MV 感染后的中枢神经系统表现可能在感染后早期出现，在急性感染的情况下脑脊髓炎。 MV 诱发的中枢神经系统疾病的第二种形式是进行性传染性脑炎，称为麻疹包涵体脑炎 (MIBE)，发生于免疫抑制患者感染后 1 至 6 个月这是麻疹感染的致命后遗症，在不断增长的人口中很常见。免疫功能低下的患者，无法接受 MV 疫苗接种或对其产生反应。 MV 诱发的神经系统疾病的第三种形式——亚急性硬化性全脑炎（SSPE）—— 即使存在中和抗体，也会在感染数年后导致致命结果。美国最近爆发的疫情表明，SSPE 的发病率可高达每 600 名受感染婴儿中就有 1 名，强调了这种疾病对于免疫能力强的人群的重要性。对于麻疹的急性或持续性中枢神经系统表现，目前尚无特效疗法。应用基础研究成果开发针对 MV CNS 感染的新抗病毒策略，基于抑制 MV 进入期间的膜融合，这一应用的主要推动力是我们的发现。脂质部分与肽（称为 C 肽）融合抑制剂的连接产生了三个主要的优点：(1) 效力增强；(2) 能够跟随病毒到达融合激活位点；我们已经证明我们的原型 C 肽可以预防致命性脑炎。我们建议评估新改进的融合的治疗效果。该策略将使用野生型菌株 MV 进行体外、离体和体内评估。和免疫受损小鼠的中枢神经系统适应菌株拟议的工作将解决两个具体问题。目标： 1. 评估 C 肽融合抑制剂的抗病毒功效：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

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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

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
影响因子：
0
作者：
通讯作者：

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

Early Permissiveness of Central Nervous System Cells to Measles Virus Infection Is Determined by Hyperfusogenicity and Interferon Pressure.

DOI：
10.3390/v15010229
发表时间：
2023-01-13
期刊：
Viruses
影响因子：
0
作者：
Ferren M;Lalande A;Iampietro M;Canus L;Decimo D;Gerlier D;Porotto M;Mathieu C
通讯作者：
Mathieu C

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