Advancing a Novel Pangenotypic Inhibitor of Human Influenza Virus to an IND

描述（由申请人提供）：我们的目标是利用我们在抗病毒研究和开发方面的集体经验来推进IND，这是一种令人兴奋的新型先导小分子抑制剂，具有泛型覆盖范围，可对抗人类已知的最常见和潜在致命的病毒感染之一-优先病原体流感病毒。我们目前的先导分子RS-8443利用专有的4'糖修饰，使天然的碱基胞嘧啶核苷成为迄今为止描述的对抗流感聚合酶最有效的分子，IC50为0.6微摩尔。此外，这种修饰使分子对流感聚合酶具有高度特异性，而对其他测试的聚合酶没有活性，从而克服了其他核苷类似物的关键潜在缺陷，并且在测试的细胞系中缺乏毒性。我们现在寻求将我们的先导化合物开发成临床阶段的药物，方法是：1)优化我们的RS-8443先导化合物，并通过分析类似物与其他天然碱基、单磷酸前药部分或新型肺活化前药部分的磷酸化动力学来确定备用化合物，这些类似物在递送到标准培养（MDCK, A549）和更相关的人类原代肺靶细胞后。然后，我们将在体外确定这些衍生物的生化活性（流感聚合酶、人类线粒体RNA和DNA γ聚合酶）和抗病毒功效；2)通过以下方法确定优化后的铅的药代动力学（PK）谱和主要代谢物：a)对大鼠和小鼠进行多剂量口服和静脉注射的药代动力学研究；b)体外（小鼠、大鼠、狗、猴和人肝细胞）和体内（小鼠、大鼠）铅主要代谢物的鉴定；3)通过以下方法确定优化先导物的关键病毒学和机制特性：a)与其他直接作用抗病毒药物（如达菲）相比，评估其体内抗病毒功效（小鼠模型）和出现耐药性的可能性；b)确定优化后的铅对金刚烷胺和达菲的多种基因型和耐药突变体的活性；c)确定优化后的铅是否通过链终止或合并起作用；4)将优化后的先导物、其主要代谢物和备用化合物进行体外ADME-Tox和初步临床前动物安全性试验，从而提名IND候选物；5)通过开展IND候选物的规模扩大活动，多剂量28天升级啮齿动物和狗研究，并准备成功的IND申请，完成IND启用研究。我们的多学科团队——包括在病毒学、核苷化学、PK和代谢物分析以及成功的早期药物开发方面具有专业知识的学者和行业合作伙伴——非常适合这项提议。成功实现我们的特定目标将产生一种令人兴奋的新药，能够保护我们免受这一关键的优先病原体，包括威胁数百万人的最致命菌株。

DESCRIPTION (provided by applicant): Our goal is to leverage our collective experience in antiviral research and development to advance towards an IND an exciting novel lead small molecule inhibitor with pangenotypic coverage against one of the most common and potentially lethal viral infections known to man--the Priority Pathogen influenza virus. Our current lead molecule, RS-8443, exploits a proprietary 4' sugar modification that makes the otherwise natural base cytosine nucleoside the most potent molecule described to date against the influenza polymerase, with an IC50 of 0.6 micromolar. Moreover, this modification renders the molecule highly specific for the influenza polymerase with no activity against other tested polymerases--thereby overcoming a key potential liability of other nucleoside analogs, and affording a lack of toxicity in tested cell lines. We now seek to develop our lead compound into a clinical stage drug by: 1) Optimizing our RS-8443 lead and identifying a back-up compound by assaying analogs with other natural bases, monophosphate prodrug moieties, or novel lung-activated prodrug moieties for their phosphorylation kinetics following delivery to standard cultured (MDCK, A549) and more relevant human primary lung target cells. We will then determine the biochemical activities (influenza polymerase, human mitochondrial RNA and DNA gamma polymerases) and antiviral efficacy of these derivatives in vitro; 2) Determining the pharmacokinetic (PK) profile and major metabolites of the optimized lead by: a) performing full rat and mouse PK studies of multiple oral and intravenous doses; and b) identifying the optimized lead's major metabolites in vitro (mouse, rat, dog, monkey and human hepatocytes) and in vivo (mouse, rat); 3) Determining key virologic and mechanistic properties of the optimized lead by: a) assessing it's in vivo antiviral efficacy (mouse model) and potential for emergence of drug resistance compared to other direct-acting antivirals (e.g. Tamiflu); b) determining the activity of the optimized lead against multiple genotypes and drug resistant mutants to amantadine and Tamiflu; and c) determining whether the optimized lead acts via chain termination vs. incorporation; 4) Nominating an IND candidate by subjecting the optimized lead, its major metabolite, and the backup compound to in vitro ADME-Tox and initial preclinical animal safety testing; 5) Completing the IND-enabling studies by conducting a scale up campaign of the IND candidate, multiple dose 28 day escalation rodent and dog studies, and preparing a successful IND application. Our multidisciplinary team--including academics and industry partners with demonstrated expertise in virology, nucleoside chemistry, PK and metabolite analysis, and successful early drug development-is ideally suited for this proposal. Successful accomplishment of our specific aims will yield an exciting novel drug capable of conferring protection against this key Priority Pathogen, including its most virulent strains that threaten millions.