Host-Directed Inhibitors of Myxovirus Replication

粘病毒复制的宿主定向抑制剂

• 批准号: 8566072
• 负责人: Richard K. Plemper
• 金额: $ 17.12万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8566072
• 关键词: AIDS/HIV problem; Acute Disease; Address; Admission activity; Adverse effects; Affect; Antiviral Agents; Antiviral Therapy; Biological Assay; Cell Line; Cells; Chemicals; Clinical; Clinical assessments; Complement; Development; Disease Management; Eligibility Determination; Evolution; Exercise; Exposure to; Failure; Family; Family member; Family suidae; Foundations; Future; Goals; Hendra Virus; Housing; Human; Human Cell Line; Human respiratory syncytial virus; Individual; Lead; Licensing; Life Cycle Stages; Lung diseases; Measles virus; Molecular; Molecular Target; Monitor; Mutation; Myxovirus; Myxovirus disease; Nipah Virus; Orthomyxoviridae; Paramyxoviridae; Paramyxovirus; Pathway interactions; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Prevention; Production; Property; Protocols documentation; Public Health; RNA Viruses; Resistance; Resistance development; Respiratory syncytial virus; Risk; Screening procedure; Solid; Staging; Technology; Therapeutic; Time; Tissues; Vaccines; Viral; Virus; Virus Replication; base; biodefense; clinically significant; cost; counterscreen; design; drug candidate; drug development; established cell line; fight against; flexibility; high throughput screening; human morbidity; human mortality; improved; indexing; influenzavirus; inhibitor/antagonist; innovation; loss of function; manufacturing process; meetings; member; next generation; novel; novel therapeutics; pandemic disease; parainfluenza virus; pathogen; pre-clinical; programs; scaffold; small molecule; therapeutic target; transmission process; vaccine efficacy; viral resistance

It is the overarching goal of this project to develop host-directed inhibitors of myxovirus replication that are designed to transform the prevalent one-drug, one-bug approach of antiviral therapy to a one-drug, multiple-bugs paradigm. This pioneering approach aims to systemically address two major challenges frequently associated with viral therapeutics: pre-existing or rapidly developing resistance to the inhibitor, and a narrow indication spectrum of many antiviral drugs, which are aggravated by cost and low flexibility of the current pharmaceutical manufacturing process, viral evolution and the emergence of novel, highly pathogenic agents. We hypothesize that these obstacles can be overcome through therapeutic targeting of host cell pathways required for virus propagation, since individual viral mutations will likely not compensate for loss-of-function of a host pathway, and viruses of related families frequently depend on overlapping sets of host components for completion of their life cycle. Considering a higher potential for drug-induced side effects that is intrinsically associated with a host-directed approach, pathogens of the myxovirus families such as influenza virus, Nipah virus and respiratory syncytial virus that are predominantly associated with acute disease emerge as particularly suitable for this therapeutic strategy, since treatment time and thus host exposure to the drug remain limited. To meet future clinical needs of antiviral therapy, this project will build on the solid foundation provided by our established anti-myxovirus program and pursue the identification and molecular characterization of innovative small-molecule antivirals to establish a tangible foundation for the future development of confirmed therapeutic candidate status towards IND-filing status. Through a combination of automated screening and chemical elaboration, our program has previously identified a pool of small-molecule hits with broadened nanomolar to low-micromolar activity against influenza virus and members of the paramyxovirus family. In this supplement project that will adhere to a set of clearly defined milestones, a novel, innovative dual-myxovirus pathogen screening protocol will be implemented to further diversify the portfolio of existing myxovirus inhibitors, alleviating the risk of early stage failure (aim 1). In search of a subset of structurally diverse lead scaffolds that meet these milestones and warrant further development, active concentrations of newly discovered and existing hits will be determined for a diverse panel of cell lines and primary cells, the effect on exposed cells profiled, the point-of-arrest in virus replication assessed, and, for selected leads with the highest antiviral potency, the broader pathogen indication spectrum, molecular target, and key ADME properties determined (aim 2). It is the goal of these exercises to identify a lead scaffold and at least one structurally unrelated alternative suitable for synthetic development and pre-clinical assessment.

该项目的总体目标是开发蜂窝病毒复制的宿主定向抑制剂，旨在将普遍的单药抗病毒治疗方法转化为一种单药，多肉袋。这种开创性方法旨在系统地解决经常与病毒疗法相关的两个主要挑战：对抑制剂的耐药或迅速发展的耐药性，以及许多抗病毒药物的狭窄指示谱，这些抗病毒药的成本受到了成本的加剧，并且由于当前的药物制造过程，病毒进化，病毒性进化和新颖的态度，具有高度传播的剂量。我们假设可以通过治疗性靶向病毒传播所需的宿主细胞途径来克服这些障碍，因为个体的病毒突变可能无法补偿宿主途径的功能丧失，并且相关家族的病毒经常取决于宿主组件完成其生命周期的重叠集。考虑到与宿主指导的方法本质上相关的药物诱导的副作用的潜力更高，诸如流感病毒，NIPAH病毒和呼吸系统依次病毒等粘菌病毒家族的病原体主要与急性​​疾病以及这种治疗时间和宿主的曝光相关，主要与急性​​疾病emerge有关，这些病毒主要适用于急性疾病。 为了满足抗病毒疗法的未来临床需求，该项目将建立在我们既定的抗毒害病毒计划提供的坚实基础的基础上，并追求创新的小分子抗病毒药的识别和分子表征，以建立确认的确认治疗候选候选状态，以建立有形的基础。通过自动筛选和化学阐述的结合，我们的程序以前已经确定了针对流感病毒的纳摩尔至低微摩尔活性的小分子命中池和帕托马病毒家族的成员。在这个将遵守一组明确定义的里程碑的补充项目中，将实施一种新颖的，创新的双粘病毒病原体筛查方案，以进一步使现有的粘液病毒抑制剂的投资组合多样化，从而减轻了早期失败的风险（AIM 1）。 In search of a subset of structurally diverse lead scaffolds that meet these milestones and warrant further development, active concentrations of newly discovered and existing hits will be determined for a diverse panel of cell lines and primary cells, the effect on exposed cells profiled, the point-of-arrest in virus replication assessed, and, for selected leads with the highest antiviral potency, the broader pathogen indication spectrum, molecular target, and key ADME确定的属性（AIM 2）。这些练习的目的是确定铅支架和至少一种结构无关的替代方案，适合合成开发和临床前评估。