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（由申请人提供）：流感感染靶标特异性病毒蛋白的当前抗病毒药。由于遗传多样性明显，不同的流感菌株表现出对销售抗激素药物的差异敏感性。此外，当前药物仍然容易受到病毒抗性快速发展的影响。本项目提议验证一种范式转移抗病毒机制，即宿主编码的Sirtuins的激活。 Sirtuins是一个七个NAD+依赖性的脱酰基酶的家族，以调节许多细胞和生物功能，包括代谢，细胞周期和寿命。基于实验，Sirtuins也可能是进化保存的广泛频谱病毒限制因子，表明在真核或原核宿主细胞中激活Sirtuins会增加包括噬菌体在内的各种病毒的生长（Koyuncu等人，2014年，MBIO，MBIO 5：E02249）。就流感疫苗而言，SIRT1和SIRT6对病毒生长的影响最大。实际上，Sirtuin激动剂的小分子筛选鉴定出SIRT1和SIRT1和6激活剂，每个激动剂都有明显的化学支架，作为有效的广谱抗病毒药。与确定的分子相比，完成的药物化学改善了SIRT1和6激活剂的抗病毒效力，并在此支架上提出了专利应用。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等奎ercetin在体内抗炎疗法中，现在已知是SIRT1激活剂。重要的是，等喹啉可以防止在培养过程中连续传递期间观察到直接作用抗病毒药amantadine和oseltamivir的病毒抗性的积累。提出的第一阶段目标是确认Sirtuin的激活提供了针对多种季节性，大流行和抗性流感和B菌株的功效，并具有对未来在细胞培养中获得的耐药性的高障碍。并重现在小鼠流感挑战中观察到的明显的抗病毒功效，该抗病毒疗效对拟议的专有激活剂进行了研究，如工具化合物，SIRT1激活剂异奎汀和白藜芦醇所证明的那样。一旦根据第一阶段的结果确定了铅系列的优先级，赠款的II期成分将进一步进行药物化学运动，以提高铅系列的效力和药代动力学特性，以在小鼠模型中提供具有口服生物可利用性的高级化合物，并具有口服生物可利用性和可比较的功效或与Oseltamivir结合使用。与Oseltamivir相比，这种产品将满足未满足的医疗需求，因为与Oseltamivir相比，这些药物应1）广泛抑制流感的所有亚型； 2）阻止对当前疗法具有抗性病毒的复制； 3）在独立治疗或组合治疗过程中大大降低病毒抗性的发展。