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（由申请方提供）：呼吸道合胞病毒（RSV）是副粘病毒家族的一员，是美国婴儿因感染性疾病住院的主要原因。在季节性流行病期间，成人经常再次感染，这为儿童经婴儿感染提供了基础，使问题更加严重。尽管进行了广泛的研究，但没有疫苗保护，目前基于抗体治疗的免疫预防仍然保留给高危患者。认识到对有效、易于应用和具有成本效益的RSV治疗药物的儿科临床需求尚未得到满足，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RSV治疗候选药物和至少一种适用于IND正式开发的机制不同的替代化合物。 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，全面的抗RSV方法询问完整的宿主-病原体相互作用组，以获得病原体导向和宿主导向的候选药物，具有最终产生可行的临床候选药物的最高前景。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，我们在试点研究中设计了一流的表达荧光素酶报告基因的重组RSV，并开发了一种创新的药物筛选方案，该方案允许在单孔环境中同时鉴定病原体导向和宿主导向的抗病毒药。该筛选的概念验证实施已经产生了具有精细毒性特征的新型病原体特异性小分子RSV进入抑制剂和细胞抗病毒防御途径的创新的宿主定向激动剂类别。两个系列的先导化合物均显示出针对致病性RSV变体的纳摩尔抑制活性。为了最大限度地提高该项目的成功前景，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），通过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，将对现有的先导化合物以及随着发现的进展而出现的新型抗RSV候选化合物进行机械表征，并鉴定其分子靶标（目的2）。具有高发展潜力的候选物将在体外效价、ADME参数和小动物药代动力学特征的指导下进行点击领先合成优化（目标3）。将在新建立的RSV感染的临床相关小鼠模型中评估先导候选物在减轻RSV细支气管炎、气道损伤、高肺病毒载量、粘液表达和肺阻塞的关键特征中的功效（目的4）。