Mucosally-delivered HA stem binding antiviral for influenza

 描述（由申请人提供）：流感是一种主要的公共卫生威胁，目前的疫苗和抗病毒药并不总是有效的。我们已经开发了一种高亲和力计算设计的抗流感蛋白（HB36.6），当鼻内给药时，在用第1组流感病毒致死性攻击的小鼠中提供了强有力的预防和治疗保护，这一结果首次证明了通过我们的计算方法设计的理论靶标转化为具有强生物效力的新的抗病毒药物。HB36.6对人类第1组流感病毒株（即H1、H5）高度有效，但对第2组病毒株（即H3、H7）无效。在本申请中，我们提出以我们对第1组结合剂的有希望的发现为基础，并通过计算设计和测试第二种抗病毒蛋白来扩大针对第1组和第2组毒株的保护效力，所述第二种抗病毒蛋白广泛结合第2组毒株，并且当与HB 36.6组合时，将提供针对广泛范围的所有流感亚型（包括禽流感和耐药毒株）的泛特异性保护。在R21阶段，我们将：鉴定计算设计的肽，其最佳地结合第2组流感亚型的HA茎区（R21，目标1）;鉴定在用组2病毒攻击的小鼠中提供预防性和治疗性保护的单一设计（目标2，R21）;并确定将优化的组2结合剂与HB 36.6（组1）组合是否在小鼠中提供针对季节性和禽流感毒株的广泛保护（目标3，R21）。如果我们在R21期然后在R33期鉴定出有效的第2组结合剂，我们将确定组合的结合剂是否在临床前雪貂模型中提供针对代表性的第1组和第2组季节性和耐药性流感毒株的上级预防性（Aim 1，R33）和治疗性（R33，Aim 2）保护功效，并确定蛋白分布与流感病毒的感染之间的关系。 和在肺中的持久性以及对抑制小鼠和雪貂肺中的病毒复制和炎症的局部作用（R33，Aim 3）。

 DESCRIPTION (provided by applicant): Influenza is a major public health threat, and current vaccines and antivirals are not always effective. We have developed a high-affinity computationally designed anti-influenza protein (HB36.6) that when administered intranasally affords strong prophylactic and therapeutic protection in mice lethally challenged with Group 1 influenza viruses, a result that demonstrated for the first time, transformation of a theoretical target designed by our computational method into a new antiviral with strong biopotency in vivo. HB36.6 is highly effective against the human Group 1 influenza strains (i.e. H1, H5) but not against Group 2 strains (i.e. H3, H7). In this application, we propose to build on our promising findings with the Group 1 binder and broaden efficacy for protection against both Group 1 and 2 strains by computationally designing and testing a second antiviral protein that broadly binds the Group 2 strains and when combined with HB36.6, will provide pan-specific protection against a wide range of all influenza subtypes including avian and drug resistant strains. In the R21 phase, we will: Identify computationally designed peptides that optimally bind the HA stem region of Group 2 influenza subtypes (R21, Aim 1); identify a single design that affords prophylactic and therapeutic protection in mice challenged with a Group 2 virus (Aim 2, R21); and determine if combining the optimized Group 2 binder with HB36.6 (Group 1) affords broad protection against seasonal and avian influenza strains in mice (Aim 3, R21). If we identify an effective group 2 binder in the R21 phase then in the R33 phase, we will determine if the combined binders afford superior prophylactic (Aim 1, R33) and therapeutic (R33, Aim 2) protective efficacy against representative Group 1 and 2 seasonal and drug resistant influenza strains in the preclinical ferret model and determine the relationship between protein distribution and persistence in the lung and localized effects on suppressing viral replication and inflammation in the mouse and ferret lung (R33, Aim 3).