SIRTUIN AGONISTS AS PAN INFLUENZA ANTIVIRALS

Sirtuin 激动剂作为泛流感抗病毒药

• 批准号: 9763415
• 负责人: Stacy Remiszewski
• 金额: $ 100万
• 依托单位: EVRYS BIO, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-08 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763415
• 关键词: Address; Agonist; Amantadine; Antiviral Agents; Bacteriophages; Biological Availability; Biological Sciences; Cell Culture Techniques; Cell Cycle; Cells; Chemicals; Development; Drug Kinetics; Family; Future; Genetic Variation; Goals; Grant; Growth; Human; Influenza; Influenza A virus; Influenza B Virus; Legal patent; Longevity; Medical; Metabolism; Morbidity - disease rate; Mus; Oral; Oseltamivir; Patients; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Plants; Property; Publishing; Resistance; Resveratrol; SIRT1 gene; Serial Passage; Sirtuins; Therapeutic; Viral; Viral Proteins; Virus; Virus Replication; anti-influenza; anti-influenza drug; anti-viral efficacy; base; comparative efficacy; experimental study; flu; improved; in vivo; lead series; mortality; mouse model; off-patent; pandemic disease; polyphenol; prevent; public health relevance; scaffold; seasonal influenza; small molecule; tool; viral resistance; virus development

? 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.

? 描述（由申请方提供）：目前用于流感感染的抗病毒药物靶向特异性病毒蛋白。由于明显的遗传多样性，不同的流感病毒株对市售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。本项目旨在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是一个由七种NAD+依赖性脱酰基酶组成的家族，已知其调节许多细胞和生物体功能，包括代谢、细胞周期和寿命。沉默调节蛋白也可以是进化上保守的广谱病毒限制性因子，这是基于以下实验：证实真核或原核宿主细胞中沉默调节蛋白的活化增加了包括噬菌体在内的多种病毒的生长（Koyuncu等人，2014，mBio 5：e02249）。在甲型流感的情况下，Sirt 1和Sirt 6对病毒生长的影响最大。事实上，sirtuin激动剂的小分子筛选确定了Sirt 1和Sirt1&6激活剂，每个都具有不同的化学支架，作为有效的广谱抗病毒药物;与筛选确定的分子相比，完整的药物化学提高了Sirt1&6激活剂的抗病毒效力，并在此支架上提交了专利申请。此外，两项独立发表的小鼠研究证明了两种植物多酚白藜芦醇和异槲皮素的体内抗流感功效，它们现在已知是Sirt 1激活剂。重要的是，异槲皮素防止了在培养物连续传代期间观察到的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。提出的I期目标是证实沉默调节蛋白活化提供针对多种季节性、大流行性和耐药性甲型和B流感毒株的功效，以及针对细胞培养物中未来获得性耐药性的高屏障;并再现在小鼠流感攻击中观察到的针对提出的专有活化剂的表观抗病毒功效，如针对工具化合物、Sirt 1活化剂异槲皮素和白藜芦醇所证明的。一旦根据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，以提高先导系列的效力和药代动力学特性，以提供具有口服生物利用度和与奥司他韦单独或联合在小鼠模型中的疗效相当的先进化合物。与奥司他韦相比，这样的产品将解决未满足的医疗需求，因为与奥司他韦相比，这些药物应1）广泛抑制甲型和B型流感的所有亚型; 2）阻断对当前疗法具有抗性的病毒的复制;和3）在单独或联合治疗期间显著减少病毒抗性的发展.