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

麻疹(MeV)导致世界范围内的疾病，尽管努力根除 疫苗，很大程度上是因为它很容易在人与人之间传播。急性甲型肝炎病毒感染 导致免疫性健忘，导致对其他感染性疾病的易感性增加 疾病。此外，罕见但严重的神经系统并发症可发展为几种 几年后，由于中枢神经系统持续感染甲型肝炎病毒而患上麻疹。 细胞免疫受损的人患上严重 麻疹，但通常不能接种，因为疫苗病毒本身可导致致命 生病了。对于急性或持续性的MeV症状，没有特定的治疗方法。一个 成功的疫苗接种运动本可以在20多年前根除MeV。 截至今天，根除麻疹的希望渺茫，2019年美国麻疹卷土重来 强调需要采取有效措施防止主机到主机的传播 疫情激增的那一刻。我们最近描述了一种新的MeV特异性融合 结合病毒特异性靶向、自组装和细胞- 膜整合导致MeV融合抑制剂的性能优于我们之前的 体外和体内的融合抑制剂。这个应用程序将测试这个新的抑制剂 防止宿主间传播，从而满足这一医疗需求。我们建议 对这些抑制剂进行化学工程，以优化1)病毒特异性靶向，2) 植入感染细胞膜；3)体内分布。我们的工作将是 使用自然的麻疹病毒感染模型在体外、体外和体内进行测试(犬 雪貂中的瘟热病毒(CDV)。 1.利用蛋白质工程优化自组装性能和 Hrc-肽融合抑制剂的抗病毒效力。 2.评价HRC多肽融合抑制剂对小鼠的保护作用 CDV在体内的感染，为临床前的发展提供概念验证。

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.