Mucosally-delivered HA stem binding antiviral for influenza

 说明(申请人提供)：流感是一个主要的公共卫生威胁，目前的疫苗和抗病毒药物并不总是有效的。我们开发了一种通过计算设计的高亲和力抗流感蛋白(HB36.6)，当给药时，对受到1型流感病毒致命攻击的小鼠提供了强大的预防和治疗保护，这一结果首次证明，由我们的计算方法设计的理论靶点在体内转化为具有强大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)非常有效，但对第2组流感病毒株(即H3、H7)无效。在这项应用中，我们建议在第一组粘合剂的基础上，通过计算设计和测试第二种抗病毒蛋白来扩大对第一组和第二组毒株的保护效力，第二种抗病毒蛋白与第二组毒株广泛结合，当与HB36.6结合时，将对包括禽流感和抗药性毒株在内的各种流感亚型提供泛特异性保护。在R21阶段，我们将：确定与第二组流感亚型(R21，Aim 1)的HA干区最佳结合的计算机设计的多肽；确定在受到第二组病毒(Aim 2，R21)攻击的小鼠中提供预防和治疗保护的单一设计；以及确定优化的第二组结合剂与HB36.6(第一组)相结合是否在小鼠中提供针对季节性和禽流感病毒株的广泛保护(Aim 3，R21)。如果我们在R21阶段确定了有效的第2组结合物，那么在R33阶段，我们将确定在临床前雪貂模型中，组合结合物是否对具有代表性的第1组和第2组季节性和抗药性流感毒株提供了更好的预防(AIM 1，R33)和治疗(R33，AIM 2)保护效果，并确定了蛋白质分布之间的关系 在小鼠和雪貂肺中抑制病毒复制和炎症的局部效应(R33，目标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).