Novel Therapeutics against Respiratory Syncytial Virus Infection

对抗呼吸道合胞病毒感染的新疗法

• 批准号: 8662435
• 负责人: Richard K. Plemper
• 金额: $ 62.29万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8662435
• 关键词: Adult; Agonist; Animals; Antibody Therapy; Antiviral Agents; Antiviral Response; Breathing; Bronchiolitis; Caregivers; Cells; Chemicals; Childhood; Clinical; Communicable Diseases; Development; Disease Management; Drug Formulations; Drug Kinetics; Elderly; Eligibility Determination; Engineering; Epidemic; Epithelial; Failure; Family; Foundations; Functional disorder; Genomics; Goals; Hospitalization; Human respiratory syncytial virus; Immunocompromised Host; In Vitro; Infant; Infection; Lead; Libraries; Ligands; Luciferases; Lung; Measles virus; Modeling; Modification; Molecular Target; Mucous body substance; Mumps virus; Mus; Myxovirus; Nature; Obstruction; Paramyxovirus; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Pilot Projects; Preclinical Drug Evaluation; Prevention; Primary Cell Cultures; Property; Proteomics; Protocols documentation; Public Health; Quantitative Structure-Activity Relationship; RNA Viruses; Recombinants; Reporter; Research; Resistance; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Risk; Safety; Series; Staging; Testing; Therapeutic; Toxic effect; Toxicity Tests; Toxicology; United States; Vaccines; Variant; Viral; Viral Load result; Virus Diseases; Virus Inhibitors; Virus Replication; analog; base; clinically relevant; cohort; cost effective; counterscreen; cytotoxicity; design; drug candidate; drug development; drug discovery; efficacy testing; high risk; high throughput screening; human morbidity; human mortality; immunoprophylaxis; improved; in vivo; inhibitor/antagonist; innovation; insight; meetings; member; mouse model; novel; novel therapeutics; pathogen; pre-clinical; prevent; programs; prophylactic; public health relevance; scaffold; screening; small molecule; small molecule libraries; success; therapeutic development; transmission process; viral resistance

DESCRIPTION (provided by applicant): Respiratory syncytial virus (RSV), a member of the paramyxovirus family, is the leading cause of infant hospitalization from infectious diseases in the United States. Regular re-infection of adults during seasonal epidemics provides the ground for caregiver-to-baby transmissions, which aggravate the problem. Despite extensive research, no vaccine protection is available and current antibody therapy-based immunoprophylaxis remains reserved for high-risk patients. Recognizing the unmet pediatric clinical need for efficacious, readily applicable and cost-effective RSV therapeutics, it is the overarching goal of this proposal to apply a rigorous drug development approach to the problem and ultimately identify an anti-RSV 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-RSV 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 engineered a first in class recombinant RSV expressing a luciferase reporter and developed an innovative drug screening protocol that allows the simultaneous identification of pathogen- directed and host-directed antivirals in a single-well setting. Proof-o-concept implementation of this screen has yielded, amongst others, a novel pathogen-specific small-molecule RSV entry inhibitor with exquisite toxicity profile and an innovative host-directed agonist class of cellular antiviral defense pathways. Lead compounds of both series show nanomolar inhibitory activity against pathogenic RSV variants. To maximize the prospect of success of this program and meet the clinical demand for effective RSV therapy, we will diversify the portfolio of anti-RSV candidates by implementing a full-scale drug screening campaign based on the newly established protocol (aim 1). In parallel, the existing leads and, as discovery advances, novel anti-RSV candidates will be mechanistically characterized and their molecular targets identified (aim 2). Candidates with high developmental potential will be subjected to hit-to-lead synthetic optimization guided by in vitro potency, ADME parameters and small-animal pharmacokinetics profiles (aim 3). The efficacy of lead candidates in alleviating key features of RSV bronchiolitis, airway damage, high lung viral load, mucus expression, and pulmonary obstruction, will be assessed in a newly established clinically relevant mouse model of RSV infection (aim 4).

描述（由申请人提供）：呼吸道合胞病毒（RSV）是副粘病毒家族的成员，是美国婴儿因传染病住院的主要原因。季节性流行期间成人经常再次感染，为护理人员向婴儿传播病毒提供了基础，从而加剧了问题。尽管进行了广泛的研究，但尚无可用的疫苗保护，并且当前基于抗体治疗的免疫预防仍然保留给高危患者。认识到儿科临床对有效、易于应用和具有成本效益的 RSV 疗法的需求尚未得到满足，本提案的总体目标是应用严格的药物开发方法来解决该问题，并最终确定一种抗 RSV 治疗候选药物和至少一种机制上的药物。适合 IND 正式开发的独特替代化合物。 目标狭窄的药物发现活动早期失败的风险很高。我们假设，全面的抗 RSV 方法询问完整的宿主-病原体相互作用组，以寻找针对病原体和宿主的候选药物，最有可能最终产生可行的临床候选药物。这是基于这样的认识：传统的针对病原体的治疗方法享有良好的临床记录，但可能会因新出现的病毒耐药性和/或狭窄的病原体适应症谱而受到损害，而针对宿主的抗病毒药物有望克服这些限制，但目前主要采用仍处于临床前开发阶段。基于我们在粘病毒抑制剂开发方面多年的专业知识，我们在试点研究中设计了表达荧光素酶报告基因的一流重组RSV，并开发了一种创新的药物筛选方案，可以同时识别病原体导向和宿主导向的病毒单孔环境中的抗病毒药物。该筛选的概念验证实施已经产生了一种新型病原体特异性小分子 RSV 进入抑制剂，具有精致的毒性特征和一种创新的宿主导向的细胞抗病毒防御途径激动剂类。这两个系列的先导化合物均表现出对致病性 RSV 变种的纳摩尔抑制活性。为了最大限度地提高该计划的成功前景并满足有效 RSV 治疗的临床需求，我们将根据新制定的方案（目标 1）实施全面的药物筛选活动，使抗 RSV 候选药物组合多样化。与此同时，现有的先导化合物以及随着发现的进展，新型抗 RSV 候选药物将得到机械表征并确定其分子靶标（目标 2）。具有高发展潜力的候选者将在体外效力、ADME 参数和小动物药代动力学特征的指导下进行从命中到先导化合物的合成优化（目标 3）。将在新建立的临床相关 RSV 感染小鼠模型中评估主要候选药物在缓解 RSV 细支气管炎、气道损伤、高肺部病毒载量、粘液表达和肺部阻塞等关键特征方面的功效（目标 4）。