Mucosally-delivered HA stem binding antiviral for influenza

粘膜递送的 HA 干结合抗流感病毒

• 批准号: 9090014
• 负责人: Deborah H. Fuller
• 金额: $ 28.84万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9090014
• 关键词: Adverse effects; Affinity; Antiviral Agents; Avian Influenza; Binding; Binding Proteins; Birds; Cause of Death; Cessation of life; Computer Simulation; Computing Methodologies; Data; Development; Disease; Dose; Drug resistance; Elderly; Ferrets; Formulation; Future; General Population; Health; Hemagglutinin; Hospitalization; Human; Immune; Immune response; Infection; Inflammation; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Lead; Lung; Marketing; Mediating; Medical; Methods; Modeling; Morbidity - disease rate; Mus; Oseltamivir; Pathogenesis; Peptides; Phase; Population; Protein Engineering; Proteins; Public Health; Recovery; Regimen; Resistance; Testing; Therapeutic; Time; Vaccination; Vaccines; Variant; Viral; Virus; Virus Replication; anti-influenza; comparative efficacy; design; drug resistant influenza; flu; in vivo; influenza virus vaccine; influenzavirus; innovation; mucosal site; novel; pandemic disease; pandemic influenza; pre-clinical; prevent; prophylactic; protective efficacy; protein distribution; receptor; research study; resistant strain; seasonal influenza; stem

 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).

 描述（由申请人提供）：流感是一个主要的公共卫生威胁，当前的疫苗和抗病毒药物并不总是有效。我们开发了一种高亲和力的计算设计的抗流感蛋白（HB36.6），当鼻内给药时可提供强有力的预防作用。以及对遭受 1 类流感病毒致死攻击的小鼠的治疗保护，这一结果首次证明，通过我们的计算方法设计的理论目标转化为具有强效的新型抗病毒药物HB36.6 对人类 1 组流感病毒株（即 H1、H5）非常有效，但对 2 组病毒株（即 H3、H7）无效。通过计算设计和测试广泛结合第 2 组菌株的第二种抗病毒蛋白，并在与 HB36.6 组合时，第 1 组结合剂并扩大针对第 1 组和第 2 组菌株的保护功效，将提供针对包括禽类和耐药菌株在内的广泛所有流感亚型的泛特异性保护。 在 R21 阶段，我们将： 确定可最佳结合第 2 组流感亚型的 HA 干区的计算设计肽（R21，目标 1）。 )；确定一种可为受到第 2 组病毒攻击的小鼠提供预防和治疗保护的单一设计（目标 2，R21），并确定是否将优化的第 2 组结合剂与HB36.6（第 1 组）为小鼠提供针对季节性和禽流感病毒株的广泛保护（目标 3，R21）如果我们在 R21 相和 R33 相中鉴定出有效的第 2 组结合物，我们将确定组合的结合物是否有效。对代表性 1 组和 2 组季节性流感病毒株和耐药流感病毒株提供卓越的预防性（目标 1、R33）和治疗性（R33、目标 2）保护功效临床前雪貂模型和确定蛋白质分布之间的关系 以及在小鼠和雪貂肺部中的持久性以及抑制病毒复制和炎症的局部效应（R33，目标 3）。