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。 与今天一样，主要是由于社会问题(例如，反政府运动)，根除不在 看得见。最近美国麻疹的死灰复燃凸显了有效预防麻疹的必要性。 在疫情激增时采取措施防止宿主之间的传播。 我们已经应用基础研究的结果来开发一种新的抗病毒策略 对于MeV，基于在MeV进入期间抑制膜融合。此应用程序将 测试我们的抗病毒方法是否可以防止宿主间传播，从而填补这一点 医疗需求。我们的策略是基于MeV融合抑制剂(即脂联 多肽)在稳定的纳米颗粒中自组装，直到到达靶细胞 它们被整合到细胞膜上。 我们最近已经证明，这一策略对SARS-CoV-2有效。 我们建议对这些抑制剂进行化学工程，以优化1)抗病毒效力，2) 多肽自组装的条件，3)插入到靶细胞上 膜，5)体内生物分布。 我们的工作将使用自然的麻疹病毒模型在体外、体外和体内进行测试。 感染(雪貂中的犬瘟热病毒-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 today, mainly due to social issue (e.g., antivaxxer movement), eradication is not in sight. The recent resurgence of measles in the U.S. highlights the need of effective measure to prevent host-to-host transmission at the moment of the outbreak surge. We have applied the results of fundamental research to develop a new antiviral strategy for MeV, based on inhibiting membrane fusion during MeV entry. This application will test whether our antiviral approach prevents inter-host transmission and therefore fill this medical demand. Our strategy is based MeV fusion inhibitors (i.e., lipid conjugated peptides) that self-assemble in stable nanoparticles until they reach the target cells were, they integrated into the cell membrane. We have recently shown that this strategy works effectively for SARS-CoV-2. We propose to chemical engineer these inhibitors to optimize 1) the antiviral potency, 2) the conditions under which the peptides self-assemble, 3) the insertion on the target cell membrane, and 5) 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.