Identification and Hit-to-Lead Development of Influenza A Virus Inhibitors

甲型流感病毒抑制剂的鉴定和先导化合物开发

• 批准号: 8955538
• 负责人: Richard K. Plemper
• 金额: $ 23.69万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8955538
• 关键词: Accounting; Address; Adult; Agonist; Animal Model; Antiviral Agents; Antiviral Response; Biophotonics; Cataloging; Catalogs; Cavia; Cell Line; Cells; Cessation of life; Chemicals; Clinical; Computer Simulation; Development; Drug Kinetics; Elderly; Ensure; Failure; Family; Foundations; Generations; Genomics; Goals; Health; Human; Infection; Influenza; Influenza A virus; Lead; Licensing; Luciferases; Lung diseases; Medical; Modeling; Modification; Molecular Target; Myxovirus; Orthomyxoviridae; Paramyxovirus; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phase; Pilot Projects; Preclinical Drug Evaluation; Program Development; Property; Prophylactic treatment; Proteomics; Protocols documentation; Public Health; Recombinants; Reporter; Resistance; Resistance profile; Staging; Structure-Activity Relationship; Testing; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Toxicity Tests; Toxicokinetics; Toxicology; Treatment Efficacy; United States; Vaccinated; Vaccines; Virus; Virus Diseases; Virus Inhibitors; Virus Replication; Virus Shedding; anti-influenza; base; counterscreen; design; drug candidate; drug development; drug discovery; follow-up; high risk; human morbidity; human mortality; immortalized cell; improved; in vivo; in vivo imaging; inhibitor/antagonist; innovation; member; mortality; mouse model; nano; novel; pandemic disease; pathogen; pre-clinical; programs; prophylactic; public health relevance; scaffold; screening; seasonal influenza; small molecule; success; transmission process; treatment effect; vaccine efficacy; viral resistance

 DESCRIPTION (provided by applicant): Influenza A virus (IAV) strains, members of the orthomyxovirus family, are the leading cause of human death from respiratory diseases despite the existence of vaccine prophylaxis. Contributing factors are poor vaccine protection of the elderly and lowered vaccine efficacy when the circulating strains differ from those included in the seasonal vaccine. The problem is further aggravated through increasing compromise of licensed anti-IAV therapeutics by pre-existing or rapidly emerging viral resistance. Recognizing the unmet clinical need for a new generation of efficacious, readily applicable IAV therapeutics, it is the overarching goal of this proposal to apply a rigorous drug development approach to the problem and ultimately identify an anti- IAV therapeutic candidate and at least one mechanistically distinct alternative compound that are suitable for IND-enabling formal development. Narrowly focused drug discovery campaigns are at high risk of early stage failure. We hypothesize that a comprehensive anti-IAV approach interrogating the full host-pathogen interactome for pathogen-directed and host-directed drug candidates has the highest prospect of ultimately yielding viable clinical candidates. This is based on the realization that traditional pathogen-directed therapeutics enjoy an excellent clinical record but can be compromised by emerging viral resistance and/or a narrow pathogen indication spectrum, whereas host-directed antivirals promise to overcome these limitations, yet are at present predominantly still in preclinical development. Building on our multiple-year expertise in the development of myxovirus inhibitors, we have in pilot studies generated a replication-competent IAV recombinant expressing a luciferase reporter and developed a drug screening protocol that allows the simultaneous identification of pathogen-directed and host- directed antivirals. Proof-of-concept implementation of the approach has yielded, amongst others, a novel host- directed agonist class of cellular antiviral defense pathways with nanomolar anti-IAV activity. To maximize the prospect of success of this program, we will in the R21 phase diversify our current portfolio of anti-IAV candidates by implementing a large-scale drug screening campaign interfaced with orthogonal counterscreens (specific aim 1). Novel anti-IAV candidates and existing leads will be mechanistically classified and a subset of distinct lead candidates short-listed based on mechanistic class and defined potency and toxicity milestones in cell lines and primary cells (specific aim 2). Selected candidates will be subjected to a hit-to-lead synthetic optimization program guided by potency, ADME/tox, and pharmacokinetic parameters, and the molecular target identified (specific aim 3). Assessment of prophylactic and therapeutic efficacy, toxicokinetic properties, the effect of treatment on the dynamics of virus host invasion, virus shedding, and transmission profiling of resistant recombinants will drive the educated selection of a clinical candidate and mechanistically and structurally distinct alternative for formal pre-clinical development (specific aim 4).

 描述（由申请方提供）：甲型流感病毒（IAV）毒株是正粘病毒家族的成员，尽管存在疫苗预防，但仍是人类因呼吸道疾病死亡的主要原因。促成因素是老年人的疫苗保护性差，以及当流行菌株与季节性疫苗中包含的菌株不同时，疫苗效力降低。通过预先存在或迅速出现的病毒耐药性对许可的抗IAV治疗剂的危害增加，该问题进一步恶化。认识到对新一代有效、易于应用的IAV治疗剂的未满足的临床需求，本提案的总体目标是对该问题应用严格的药物开发方法，并最终确定抗IAV治疗候选物和至少一种适合IND使能正式开发的机制上不同的替代化合物。 狭隘的药物发现活动在早期阶段失败的风险很高。我们假设，一个全面的抗IAV的方法，询问完整的宿主-病原体相互作用组的病原体导向和宿主导向的候选药物具有最高的前景，最终产生可行的临床候选药物。这是基于这样的认识，即传统的病原体导向的治疗剂享有良好的临床记录，但可能受到新出现的病毒耐药性和/或狭窄的病原体适应症谱的影响，而宿主导向的抗病毒药物有望克服这些限制，但目前主要仍处于临床前开发阶段。基于我们在开发粘病毒抑制剂方面的多年专业知识，我们在试点研究中产生了表达荧光素酶报告基因的可复制IAV重组体，并开发了允许同时鉴定病原体导向和宿主导向的抗病毒药的药物筛选方案。该方法的概念验证实施已经产生了具有纳摩尔抗IAV活性的新型宿主定向激动剂类的细胞抗病毒防御途径等。为了最大限度地提高该计划的成功前景，我们将在R21阶段通过实施与正交反筛选（具体目标1）相结合的大规模药物筛选活动，使我们目前的抗IAV候选药物组合多样化。将对新型抗IAV候选药物和现有先导药物进行机械分类，并基于细胞系和原代细胞中的机械分类和定义的效力和毒性里程碑（具体目标2），将不同先导药物候选药物的子集列入短名单。选择的候选物将接受由效价、ADME/tox和药代动力学参数指导的命中先导合成优化程序，并鉴定分子靶标（具体目标3）。评估预防和治疗有效性、毒代动力学特性、治疗对病毒宿主入侵动力学的影响、病毒脱落和耐药重组体的传播特征将推动对临床候选药物和机制和结构上不同的替代药物进行有针对性的选择，以进行正式的临床前开发（具体目标4）。