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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.

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

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

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

DOI：
发表时间：
2019
期刊：
Journal of Nanomedicine & Nanotechnology
影响因子：
0
作者：
E. Martínez
通讯作者：
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
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

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