SIRTUIN AGONISTS AS PAN INFLUENZA ANTIVIRALS

？ 描述(由申请人提供)：目前针对流感感染的抗病毒药物针对特定的病毒蛋白。由于显著的遗传多样性，不同的流感毒株对市场上销售的抗流感药物表现出不同的敏感性。此外，目前的药物仍然容易受到病毒耐药性快速发展的影响。本项目建议验证一种范式转换的抗病毒作用机制，即激活宿主编码的sirtuins。Sirtuins是一个由七个依赖NAD+的脱酰基酶组成的家族，已知调节许多细胞和组织功能，包括新陈代谢、细胞周期和寿命。Sirtuins也可能是进化上保守的广谱病毒限制因子，基于实验表明，在真核或原核宿主细胞中sirtuins的激活促进了包括噬菌体在内的各种病毒的生长(Koyuncu等人)。2014年，mBio 5：e02249)。就甲型流感而言，Sirt1和SIRT6对病毒生长的影响最大。事实上，对sirtuin激动剂的小分子筛选确定了Sirt1和Sirt1&6激活剂，每个都具有不同的化学支架，是有效的广谱抗病毒药物；与筛选确定的分子相比，完成的药物化学改进了Sirt1&6激活剂的抗病毒效力，并在该支架上提交了专利申请。此外，两项独立发表的小鼠研究表明，两种植物多酚白藜芦醇和异槲皮素在体内具有抗流感功效，目前已知这两种植物多酚是Sirt1激活剂。重要的是，异栎素防止了在培养连续传代过程中观察到的对直接作用抗病毒药物金刚烷胺和奥司他韦的病毒耐药性的积累。拟议的第一阶段目标是证实sirtuin激活能够有效对抗多种季节性、大流行和耐药的甲型和乙型流感病毒株，并在细胞培养中针对未来获得的耐药性具有高屏障；以及重现建议专利激活剂在小鼠流感挑战中所观察到的明显抗病毒效果，如工具化合物Sirt1激活剂异槲皮素和白藜芦醇所证明的那样。一旦基于第一阶段的结果确定了先导系列的优先顺序，赠款的第二阶段部分将进一步推进药物化学活动，以改善先导系列的效力和药代动力学特性，从而在小鼠模型中提供具有口服生物利用度和类似疗效的先进化合物，或者与奥司他韦联合使用。与奥司他韦相比，这种产品将解决未得到满足的医疗需求，因为与奥司他韦相比，这些药物应该1)广泛抑制所有亚型流感A和B；2)阻止对当前疗法产生抗药性的病毒的复制；3)在单独或联合治疗期间极大地减少病毒抗药性的发展。

? DESCRIPTION (provided by applicant): Current antivirals for influenza infection target specific viral proteins. Due to marked genetic diversity, different strains of influenza demonstrate differential sensitivity to marketed anti-influenza drugs. Additionally, current drugs remain vulnerable to the rapid development of virus resistance. The present project proposes to validate a paradigm-shifting antiviral mechanism-of-action, the activation of host-encoded sirtuins. Sirtuins are a family of seven NAD+-dependent deacylases known for regulating numerous cellular and organismal functions, including metabolism, cell cycle and longevity. Sirtuins may also be evolutionarily conserved broad- spectrum viral restriction factors based on experiments demonstrating that activation of sirtuins in eukaryotic or prokaryotic host cells increases growth of diverse viruses including bacteriophages (Koyuncu et al. 2014, mBio 5:e02249). In the case of influenza A, Sirt1 and Sirt6 have the largest effects on virus growth. Indeed a small molecule screen for sirtuin agonists identified a Sirt1 and a Sirt1&6 activator, each with a distinct chemical scaffold, as potent broad-spectrum antivirals; completed medicinal chemistry improved the antiviral potency of the Sirt1&6 activator compared to the screen identified molecule and a patent application was filed on this scaffold. In addition, two independently published mouse studies demonstrate in vivo anti-influenza efficacy for two plant polyphenols resveratrol and isoquercetin that are now known to be Sirt1 activators. Importantly, isoquercetin prevented the accumulation of viral resistance observed for direct-acting antivirals amantadine and oseltamivir during serial passage in culture. Proposed Phase I goals are to confirm sirtuin activation provides efficacy against multiple seasonal, pandemic, and resistant influenza A and B strains, and a high barrier against future acquired resistance in cell culture; and to reproduce the apparent antiviral efficacy observed in mouse influenza challenge for proposed proprietary activators as was demonstrated for tool compounds, Sirt1 activators isoquercetin and resveratrol. Once a lead series is prioritized based on the Phase I results, the Phase II component of the grant will further progress a medicinal chemistry campaign to improve the potency and pharmacokinetic properties of the lead series to deliver advanced compounds with oral bioavailability and comparable efficacy as stand-alone or in combination with oseltamivir in the mouse model. Such a product will address unmet medical need compared to oseltamivir, because compared to oseltamivir, these drugs should 1) broadly inhibit all subtypes of influenza A and B; 2) block the replication of viruses resistant to current therapies; and 3) dramatically reduce the development of viral resistance during stand- alone or combination treatment.