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

描述（由申请人提供）：尽管在疫苗设计、制造和分销方面有所改进，甲型流感感染仍然是一个重大的公共卫生问题。2013年2月美国疾病控制与预防中心“季节性流感疫苗有效性临时调整估计”报告称，针对甲型流感和乙型流感感染，疫苗的总体有效性分别为56%和67%，而对呼吸道并发症高危人群65岁以上老年人的有效性则大大降低，仅为9%。值得注意的是，该报告“强调了流感疫苗继续取得进展的必要性，特别是要增加对老年人的保护作用”，并指出，“这个季节……老年人的抗病毒治疗尤其重要。最好在发病后48小时内……”过去这个季节对季节性流感的保护显然一般，这也再次强调了出现高致病性大流行毒株的威胁，以及流感可能被用作生物战的工具。目前可用的用于流感感染的直接抗病毒药物仍然容易受到病毒耐药性发展的影响。本项目提出验证一种范式转移的抗病毒作用机制，同时调节特定宿主编码的Sirtuins。Sirtuins是依赖于NAD+的去乙酰化酶，通常以其在热量限制和红酒成分白藜芦醇中观察到的延长寿命的作用而闻名。该资助提案的初步证据表明，利用工具化合物和已完成的Sirtuin调节剂高通量筛选的专利靶点对Sirtuin进行药理学调节，可以有效地阻断培养物中多种人类致病性病毒的生长，包括甲型流感。事实上，与文献中描述的Sirtuin作为代谢调节剂的机制一致，它可以在代谢改变的肿瘤中特异性地诱导细胞凋亡，而不是正常细胞。Sirtuin调节似乎能有效清除病毒感染

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.