Development of novel broad-spectrum influenza A inhibitors

新型广谱甲型流感抑制剂的开发

• 批准号: 8123976
• 负责人: Ken J McCormack
• 金额: $ 22.32万
• 依托单位: ARISAN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2012-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8123976
• 关键词: Accounting; Adopted; Amantadine; Amantadine resistance; Antiviral Agents; Area; Binding Sites; Biological Assay; Cell Line; Cell-Mediated Cytolysis; Cells; Cessation of life; Collection; Combination Drug Therapy; Combined Modality Therapy; Complement; Data; Dependence; Development; Disease Outbreaks; Drug Design; Drug resistance; Epidemic; Exhibits; Fluorescent Dyes; Health; Hospitalization; Human; Individual; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Inhibitory Concentration 50; Libraries; Methods; Mono-S; Mutation; National Institute of Allergy and Infectious Disease; Neuraminidase inhibitor; Oseltamivir; Pharmaceutical Preparations; Pharmacotherapy; Prevention; Production; Property; Prophylactic treatment; Protons; Reporting; Research; Resistance; Risk; Sampling; Seasons; Series; Site; Testing; Tetanus Helper Peptide; Therapeutic; Time; Toxic effect; Vaccination; Vaccines; Validation; Variant; Viral; Virus Diseases; anti-influenza drug; base; combat; combinatorial; comparative; computer studies; cytotoxicity; flu; influenza outbreak; inhibitor/antagonist; innovation; interest; lead series; novel; pandemic disease; pandemic influenza; phase 2 study; resistant strain; response; scaffold; seasonal influenza; small molecule; small molecule libraries

DESCRIPTION (provided by applicant): The influenza A virus represents one of the greatest global human health risks. While vaccines provide significant protection from seasonal flu infections they still account for an estimated 36,000 deaths and 200,000 hospitalizations per year in the US alone. Furthermore, the inherent time involved in development, production and distribution of vaccines limits their potential efficacy against rapidly emerging outbreaks. Two classes of drugs have been approved for influenza prophylaxis and treatment. Alarmingly, the past decade has witnessed the emergence of drug resistant as well as novel 2009 pandemic (H1N1) and highly pathogenic (H5N1) strains of influenza A. Amantadine- resistance has become so widespread the amantadanes have become all but ineffective and some flu strains have already exhibited significant resistance to neuraminidase inhibitors. Optimally, as adopted for the treatment of other viral diseases, combination drug therapies would be used to provide the most effective prophylaxis and treatment and to inhibit the emergence of additional drug- resistances. Thus, there is an urgent need for new and more effective antiviral mono- and combination therapies. Here we provide an innovative approach to identify inhibitors of both amantadine-sensitive and -resistant forms of the M2 proton channel to provide novel broad-spectrum therapeutics. Using this approach we provide a platform for the identification of new inhibitory compounds acting at novel sites of a clinically validated influenza A target for the development of new mono- and combination antiviral drug therapies; a designated NIAID high priority area of interest. PUBLIC HEALTH RELEVANCE: Over the past decade the emergence of a number of drug-resistant and/or highly pathogenic variants of influenza have dramatically increased the potential impact of influenza infection. This proposal details an innovative approach to identify much needed novel inhibitors and potential therapeutics for the prevention and treatment of influenza A infection for mono and combination drug therapies.

描述（由申请人提供）：甲型流感病毒是全球最大的人类健康风险之一。尽管疫苗可以有效预防季节性流感感染，但仅在美国，每年仍导致约 36,000 人死亡和 200,000 人住院。此外，疫苗的开发、生产和分发所涉及的固有时间限制了它们针对迅速出现的疫情的潜在功效。两类药物已被批准用于预防和治疗流感。令人担忧的是，过去十年出现了耐药性以及 2009 年大流行 (H1N1) 和高致病性 (H5N1) 甲型流感病毒株。金刚烷胺耐药性已变得如此普遍，以至于金刚烷胺几乎无效，并且一些流感病毒株已经表现出对神经氨酸酶抑制剂的显着耐药性。最理想的是，正如治疗其他病毒性疾病所采用的那样，联合药物疗法将用于提供最有效的预防和治疗，并抑制其他耐药性的出现。因此，迫切需要新的、更有效的抗病毒单一疗法和联合疗法。在这里，我们提供了一种创新方法来鉴定 M2 质子通道金刚烷胺敏感和耐药形式的抑制剂，以提供新颖的广谱疗法。利用这种方法，我们提供了一个平台，用于鉴定作用于经临床验证的甲型流感靶点的新位点的新抑制化合物，以开发新的单一和组合抗病毒药物疗法；指定的 NIAID 高度优先关注领域。 公共卫生相关性：过去十年中，多种耐药和/或高致病性流感变种的出现极大地增加了流感感染的潜在影响。该提案详细介绍了一种创新方法，以确定急需的新型抑制剂和潜在疗法，用于预防和治疗甲型流感感染的单一和联合药物疗法。