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

说明(申请人提供)：尽管疫苗设计、制造和分发有所改进，但甲型流感感染仍然是一个重大的公共卫生问题。美国疾病控制与预防中心2013年2月发表的《季节性流感疫苗效力中期调整估计》报告称，甲型和乙型流感疫苗的整体效力分别为56%和67%，而65岁以上的老年人的效力大大降低，仅为9%，这是呼吸道并发症的高危人群。值得注意的是，该报告“强调了流感疫苗持续进步的必要性，尤其是增加老年人的保护性福利”，并指出，“这个季节……针对老年人的抗病毒治疗尤为重要……最好是在发病后48小时内……”在过去的这个季节，对季节性流感的明显平庸保护也再次强调了高致病性大流行毒株出现的威胁，以及流感可能被用作生物战的媒介。目前，现有的治疗流感感染的直接作用抗病毒药物仍然容易产生病毒耐药性。本项目建议验证一种范式转换的抗病毒作用机制，即同时调制特定宿主编码的sirtuins。Sirtuins是依赖于NAD+的脱乙酰酶，更广为人知的是它们在观察到的卡路里限制和红酒配料白藜芦醇的延长寿命效应中的作用。这项拨款提案的初步证据表明，通过工具化合物和来自完整sirtuin调节剂高通量筛选的专有靶点的药物sirtuin调制，有效地阻止了培养中包括流感A在内的多种人类致病病毒的生长。事实上，与文献中描述的sirtuins作为代谢调节因子的机制一致，sirtuin调制似乎可以有效地清除病毒感染。sirtuin调节剂可以诱导新陈代谢改变的肿瘤而不是正常细胞中的细胞凋亡。 通过特定的凋亡消除病毒感染的细胞，同时使未感染的细胞保持完好。建议的SBIR第一阶段目标是验证筛选中确定的专利化学支架，并验证Sirtuin调制作为一种有效的宿主定向泛流感抗病毒机制，具有体内治疗窗口以及与现有流感抗病毒药物相比减少的获得性耐药性。观察到的病毒清除是显著的，实际上可能导致症状改善，远远超出早期给药窗口(感染患者为48小时)，在下游SBIR第二阶段使用预测人类状况的临床前模型进行测试。最初的目标患者群体实际上可能包括对疫苗免疫反应较差的老年人，但无论如何，拟议的宿主靶向抗病毒药物预计将在泛流感有效性和获得性耐药性方面补充现有疫苗和抗病毒药物。

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.