Novel Therapeutics against Respiratory Syncytial Virus Infection

描述（由申请人提供）：呼吸道合胞病毒（RSV）是副粘病毒家族的一员，是美国婴儿因传染病住院的主要原因。在季节性流行期间，成年人经常再次感染病毒，这为照料者向婴儿传播提供了基础，从而加剧了问题。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保留给高危患者。认识到儿科临床对有效、易于应用且具有成本效益的RSV治疗药物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这一问题，并最终确定一种抗RSV治疗候选药物和至少一种机制独特的替代化合物，适合于ind的正式开发。狭隘的药物发现运动在早期阶段失败的风险很高。我们假设，一种全面的抗rsv方法对病原体导向和宿主导向的候选药物进行完整的宿主-病原体相互作用组的询问，最终产生可行的临床候选药物的前景最大。这是基于认识到传统的病原体导向治疗具有良好的临床记录，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。基于我们在黏液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一种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，可以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物。该筛选的概念验证实施已经产生了一种新的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定向激动剂类细胞抗病毒防御途径。这两个系列的先导化合物对致病性RSV变异均表现出纳摩尔级的抑制活性。为了最大限度地提高这一项目的成功前景，并满足有效治疗RSV的临床需求，我们将根据新建立的方案实施全面的药物筛选活动，使抗RSV候选药物组合多样化（目标1）。与此同时，现有的线索以及随着发现的进展，新的抗rsv候选物将被机制表征并确定其分子靶点（目的2）。具有高发育潜力的候选药物将在体外效价、ADME参数和小动物药代动力学特征的指导下进行先导合成优化（目标3）。主要候选药物在缓解RSV细支气管炎、气道损伤、高肺病毒载量、粘液表达和肺阻塞等关键特征方面的疗效将在新建立的RSV感染临床相关小鼠模型中进行评估（目的4）。

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).