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).

 说明(申请人提供)：甲型流感病毒(IAV)是正粘病毒家族的成员，尽管存在疫苗预防措施，但它们仍是人类死于呼吸系统疾病的主要原因。促成因素是老年人疫苗保护不力，以及当流行毒株与季节性疫苗中包括的毒株不同时，疫苗效力降低。由于预先存在或迅速出现的病毒耐药性，授权的抗IAV治疗药物越来越多地受到损害，这一问题进一步加剧。认识到对新一代有效、易于应用的IAV疗法的临床需求尚未得到满足，这项建议的首要目标是应用严格的药物开发方法来解决这个问题，并最终确定一种抗IAV治疗候选药物和至少一种机械上不同的替代化合物，这些化合物适合于IND-Enabling正式开发。狭隘的药物发现活动早期失败的风险很高。我们假设，一种全面的抗IAV方法询问完整的宿主-病原体相互作用组以寻找病原体导向和宿主导向的候选药物，最终产生可行的临床候选药物的可能性最高。这是基于这样一种认识，即传统的病原体导向疗法享有良好的临床记录，但可能会受到新出现的病毒耐药性和/或病原体适应症谱的影响，而宿主导向抗病毒药物有望克服这些限制，但目前仍主要处于临床前开发阶段。基于我们在粘病毒抑制剂开发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具有复制能力的IAV重组体，并开发了一种药物筛选方案，允许同时鉴定病原体导向和宿主导向的抗病毒药物。该方法的概念验证实施已经产生了一种新的宿主定向的激动剂类具有纳米分子抗IAV活性的细胞抗病毒防御途径。为了最大限度地提高这一计划的成功前景，我们将在R21阶段通过实施与正交反筛选(特定目标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。将对新的抗IAV候选药物和现有的铅进行机械分类，并根据机械分类和确定的细胞系和原代细胞中的效力和毒性里程碑(具体目标2)，将一些不同的候选铅列入候选名单。选定的候选人将接受一项由效力、ADME/TOX和药代动力学参数指导的Hit-to-Lead综合优化计划，并确定分子靶标(特定目标3)。对预防和治疗效果、毒代动力学特性、治疗对病毒宿主入侵动态的影响、病毒脱落和耐药重组体的传播概况的评估将推动对正式临床前开发的临床候选和机械和结构上不同的替代方案的有意义的选择(具体目标4)。