Design of fusion inhibitors to block measles host-to-host infection

麻疹（MeV）在世界范围内引起疾病，尽管人们努力根除麻疹， 疫苗，主要是因为它很容易在人与人之间传播。急性MeV感染 导致免疫健忘症，从而增加对其他感染性疾病的易感性。 疾病此外，罕见但严重的神经系统并发症可能会发展成几种 由于中枢神经系统的持续MeV感染，麻疹后10年。 细胞免疫力受损的人患严重的 麻疹，但往往不能接种疫苗，因为疫苗病毒本身可导致致命的 病对于急性或持续性MeV表现没有特异性治疗。一 成功的疫苗接种运动可以在20多年前消除MeV。 到今天为止，消灭麻疹还遥遥无期，2019年美国麻疹的死灰复燃 强调需要采取有效措施，在 疫情激增的时刻。我们最近描述了一种新的MeV特异性融合 结合了病毒特异性靶向、自组装和细胞- 膜整合导致MeV融合抑制剂，优于我们以前的 融合抑制剂在体外和体内。这项应用将测试这种新的抑制剂是否 防止宿主间传播，从而满足这一医疗需求。我们建议 化学工程这些抑制剂，以优化1）病毒特异性靶向，2） 在感染细胞膜上的插入，和3）体内生物分布。我们的工作并 使用麻疹病毒感染的自然模型（犬）进行体外、离体和体内测试 犬瘟热病毒-CDV-在雪貂）。 1.利用蛋白质工程优化自组装特性， HRC-肽融合抑制剂的抗病毒效力。 2.为了评估HRC肽融合抑制剂提供的保护， CDV体内感染，并为临床前开发提供概念验证。

Measles (MeV) causes disease worldwide despite efforts towards eradication by vaccine, largely because it is spread so readily between people. Acute MeV infection causes immune amnesia, resulting in increased susceptibility to other infectious diseases. In addition, rare but severe neurological complications can develop several years after measles due to persistent MeV infection of the central nervous system. People with impaired cellular immunity are at increased risk of developing severe measles, but often cannot be vaccinated since the vaccine virus itself can lead to fatal illness. There is no specific therapy for acute or persistent MeV manifestations. A successful vaccination campaign could have eradicated MeV more than 20 years ago. As of today, eradication is not in sight and the resurgence of measles in the U.S. 2019 highlights the need for effective measures to prevent host-to-host transmission at the moment of the outbreak surge. We have recently described a new MeV-specific fusion inhibitor peptide that combines viral-specific targeting, self-assembling, and cell- membrane integration leading to a MeV fusion inhibitor that outperformed our previous fusion inhibitors in vitro and in vivo. This application will test whether this new inhibitor prevents inter-host transmission and therefore fill this medical demand. We propose to chemical engineer these inhibitors to optimize 1) the viral-specific targeting, 2) the insertion on infected cells membrane, and 3) in vivo biodistribution. Our work will be tested in vitro, ex vivo, and in vivo using a natural model of morbillivirus infection (Canine Distemper Virus -CDV- in Ferrets). 1. To use protein engineering to optimize the self-assembling properties and antiviral potency of HRC-peptide fusion inhibitors. 2. To evaluate the protection afforded by HRC peptide fusion inhibitors against CDV infection in vivo and provide proof of concept for pre-clinical development.