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宿主导向的黏液病毒复制抑制剂，旨在将流行的一药一虫抗病毒治疗方法转变为一药多虫范式。这种开创性的方法旨在系统地解决与病毒疗法经常相关的两个主要挑战：预先存在或迅速发展的对抑制剂的耐药性，以及许多抗病毒药物的狭窄适应症，这是由于当前制药工艺的成本和低灵活性，病毒进化和新型高致病性药物的出现而加剧的。我们假设这些障碍可以通过针对病毒传播所需的宿主细胞通路的治疗性靶向来克服，因为单个病毒突变可能无法弥补宿主通路的功能丧失，并且相关家族的病毒经常依赖于重叠的宿主组分集来完成其生命周期。考虑到药物引起的副作用的可能性较高，这与宿主导向的方法内在相关，黏液病毒家族的病原体，如流感病毒、尼帕病毒和呼吸道合胞病毒，主要与急性疾病相关，因此特别适合这种治疗策略，因为治疗时间和宿主接触药物的时间仍然有限。