Host-Targeted Mechanism of Action for Treatment of Seasonal and Pandemic Influenz

治疗季节性和大流行性流感的宿主靶向作用机制

• 批准号: 8647074
• 负责人: Emre Koyuncu
• 金额: $ 22.5万
• 依托单位: EVRYS BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-15 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647074
• 关键词: Adult; Affect; Animal Model; Antiviral Agents; Antiviral resistance; Apoptosis; Apoptotic; Applications Grants; Avian Influenza; Biological Assay; Biological Sciences; Biological Warfare; Birds; Caloric Restriction; Cells; Centers for Disease Control and Prevention (U.S.); Chemicals; Chicago; Clinic; Clinical; Complement; Data; Deacetylase; Development; Disease; Dose; Effectiveness; Elderly; Enzyme Inhibition; Enzymes; Genetic; Genome; Goals; Growth; Hour; Human; Immune response; In Vitro; Infection; Influenza; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H5N1 Subtype; Influenza A virus; Inhibitory Concentration 50; Lead; Left; Life Cycle Stages; Literature; Longevity; Maximum Tolerated Dose; Measures; Medical; Metabolism; Morbidity - disease rate; Mutation; Normal Cell; Onset of illness; Oseltamivir; Patients; Persons; Pharmaceutical Preparations; Phase; Plasma; Population; Populations at Risk; Pre-Clinical Model; Property; Public Health; Reporting; Research Institute; Resistance; Resistance development; Resistance profile; Resveratrol; Risk; Role; Seasons; Sirtuins; Site; Small Business Innovation Research Grant; Structure; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Index; Time; Vaccine Design; Vaccines; Validation; Variant; Viral; Virulent; Virus; Virus Diseases; Work; anti-influenza drug; base; cell killing; commercialization; cytotoxic; enzyme activity; flu; high throughput screening; in vitro Assay; in vivo; indexing; influenza virus vaccine; influenzavirus; inhibitor/antagonist; meetings; mortality; mouse model; novel; novel therapeutics; pandemic disease; pandemic influenza; patient population; prevent; public health relevance; red wine; resistant strain; respiratory; response; scaffold; seasonal influenza; small molecule; symptomatic improvement; tool; tumor; vaccination strategy; vaccine effectiveness; viral resistance

DESCRIPTION (provided by applicant): Despite improvements in vaccine design, manufacture, and distribution, influenza A infection remains a significant public health concern. The February 2013 CDC "Interim Adjusted Estimates of Seasonal Influenza Vaccine Effectiveness" reported overall vaccine effectiveness of 56% and 67% against influenza A and B infections, respectively, with much reduced effectiveness of 9% observed for 65+ elderly, an at-risk population for respiratory complications. Of note, the report "reinforces the need for continued advances in influenza vaccines, especially to increase protective benefits for older adults" and notes, "this season...antiviral treatment of elderly adults is especially important...preferably within 48 hours after illness onset..." This past season's apparent mediocre protection against seasonal influenza also reemphasizes the threat of emergence of highly pathogenic pandemic strains as well as the potential use of influenza as a vehicle for biological warfare. Currently available direct acting antivirals for influenza infection remain vulnerable to the development of virus resistance. The present project proposes to validate a paradigm-shifting antiviral mechanism-of-action, the simultaneous modulation of specific host-encoded Sirtuins. Sirtuins are NAD+-dependent deacetylases more generally known for their role in the observed life-span increasing effects of caloric restriction and the red wine ingredien, resveratrol. Preliminary evidence for this grant proposal demonstrates that pharmacological Sirtuin modulation with tool compounds and proprietary hits from a completed sirtuin-modulator high- throughput screen, effectively blocks the growth of multiple human pathogenic viruses in culture, including influenza A. In fact, consistent with described mechanisms of Sirtuins as regulators of metabolism in the literature that can induce apoptosis specifically in metabolically-changed tumor but not normal cells, Sirtuin modulation appears to efficiently clear virus infection by specific apoptotic elimination of virally-infected cells while leaving uninfected cells intact i culture. Proposed SBIR Phase 1 goals are to validate proprietary chemical scaffolds identified in the screen and to validate Sirtuin modulation as an efficient host-targeted pan- influenza antiviral mechanism with demonstrated window of therapy in vivo as well as a reduced acquired- resistance profile compared to existing influenza antivirals. The observed viral clearance is remarkable and may in fact result in symptomatic improvements well beyond an early window of administration (48 hours in infected patients) to be tested in downstream SBIR Phase 2 using preclinical models predictive of the human condition. An initial target patient population, could in fact comprise older adults with poor immune response to vaccines, but in any case, the proposed host-targeted antivirals are predicted to complement existing vaccine and antivirals in pan-influenza effectiveness and acquired-resistance profile.

描述（由申请人提供）：尽管疫苗设计，制造和分销有所改善，但流感A感染仍然是一个重大的公共健康问题。 2013年2月的CDC“季节性流感疫苗有效性的临时调整估计值分别报告了56％和67％的疫苗有效性，分别针对流感疫苗和B感染，而65岁以上的老年人观察到的9％的有效性大大降低，这是呼吸疾病的处于风险的人群中。值得注意的是，该报告“增强了流感疫苗的持续进展需求，特别是为了增加对老年人的保护益处的需求”和注释：“本季……对老年人的抗病毒待遇……尤其重要……最好在疾病发作后的48小时内……最好在过去的季节后48小时内……“本赛季明显的平均季节性保护也对季节性造成了高度的危险，同时又遭受了高度的影响。生物战的车辆。目前可用于流感感染的直接作用抗病毒药仍然容易受到病毒抗性的发展。本项目提议验证范式转移抗病毒机理，即对特定宿主编码的Sirtuins的同时调节。 Sirtuins是NAD+依赖性的脱乙酰基酶，以其在观察到的寿命中的作用而闻名，它们在热量限制和红酒Ingredien，白藜芦醇中的作用增加。该赠款提案的初步证据表明，来自完整的Sirtuin-调制器高吞吐量筛查的药理Sirtuin调节和专有式筛选，有效地阻止了培养中多种人类致病性病毒的增长，包括流感A.，包括流感A.，实际上，与Sirtuins As Condation As Condation of Metabirist of Metabirism of Metabirism of Metaborismoliss of Metaborism oselismolism ass of Metaborismolism issul of Metaborism ass of Metaborism oselismismolism ass of Metaborism ass of Metaborism ass的生长，这是一致的。代谢变化的肿瘤但不是正常细胞，Sirtuin调节似乎有效清除病毒感染 通过特异性凋亡消除病毒感染的细胞，同时使未感染的细胞完整I培养。提出的SBIR第1阶段目标是验证屏幕上确定的专有化学支架，并验证Sirtuin调制为有效的宿主靶标pan-Pan-pan-Pan-pan-pan-pan-pan-pan-pan-pan-pan-pan-typoiral in Vivo的窗口，以及与现有的流感抗病毒剂相比，降低了所获得的抗药性。观察到的病毒清除非常明显，实际上可能会导致有症状的改善，远远超出了早期给药窗口（感染患者48小时），使用临床前阶段2在下游SBIR 2阶段使用临床前模型，可以预测人类状况。最初的目标患者人群实际上可能包括对疫苗免疫反应不佳的老年人，但无论如何，预计拟议的宿主靶向抗病毒药会补充泛素疫苗的现有疫苗和抗病毒药，并获得了泛素的有效性和获得的耐药性。