Novel Therapeutics against Respiratory Syncytial Virus Infection

描述(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的定期再次感染为照料者向婴儿传播提供了基础，这加剧了问题。尽管进行了广泛的研究，但目前还没有疫苗保护措施，目前基于抗体疗法的免疫预防仍然只针对高危患者。认识到儿科对有效、易于应用和成本效益高的RSV疗法的需求尚未得到满足，这项建议的首要目标是应用严格的药物开发方法来解决这个问题，并最终确定一种抗RSV治疗候选药物和至少一种机械上不同的替代化合物，这些化合物适合于IND-Enabling正式开发。狭隘的药物发现活动早期失败的风险很高。我们假设，一种全面的抗RSV方法询问完整的宿主-病原体相互作用组以寻找病原体导向和宿主导向的候选药物，最终产生可行的临床候选药物的可能性最高。这是基于这样一种认识，即传统的病原体导向疗法享有良好的临床记录，但可能会受到新出现的病毒耐药性和/或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，但目前仍主要处于临床前开发阶段。基于我们在粘病毒抑制剂开发方面的多年专业知识，我们在试点研究中设计了一种表达荧光素酶报告基因的一流重组RSV，并开发了一种创新的药物筛选方案，允许在单一孔环境中同时识别病原体导向和宿主导向的抗病毒药物。这一筛选的证明o概念的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，具有精致的毒性分布和一种创新的宿主定向的激动剂类别的细胞抗病毒防御途径。这两个系列的先导化合物都显示出对致病RSV变种的纳摩尔抑制活性。为了最大限度地提高这一计划的成功前景并满足对有效RSV治疗的临床需求，我们将根据新建立的方案(目标1)实施全面的药物筛选活动，从而使抗RSV候选药物的组合多样化。同时，现有的先导和随着发现的进展，新的抗呼吸道合胞病毒候选药物将被机械地表征并确定它们的分子靶标(目标2)。具有高开发潜力的候选人将接受由体外效力、ADME参数和小动物药代动力学曲线指导的Hit-to-Lead综合优化(目标3)。将在新建立的RSV感染的临床相关小鼠模型中评估候选先导药物在缓解RSV毛细支气管炎、呼吸道损伤、高肺病毒载量、粘液表达和肺梗阻等关键特征方面的有效性(目标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).