Inhalation Therapy Platform for Coronavirus Infection Treatment

项目摘要/摘要 新出现的SARS-CoV-2冠状病毒证明了肺部病原体对人类的致命威胁 一个暴露在暴露中的天真世界，没有现成的疫苗或疗法。有效的发展 疫苗提供了关键的预防产品，但由于治疗缓慢和不完整，治疗仍然很重要。 世界范围内的报道，以及耐药性变种的出现。尤其需要综合治疗。 能够以服从全球设置的格式部署的平台，并且需要能够快速部署的平台 针对未来的肺部威胁而开发的。该项目旨在开发一种多功能的吸入性治疗方法 对抗新冠肺炎疾病和未来冠状病毒的平台。它是为喷雾器而设计的，可分发 吸入装置，以最大限度地提高肺部的药物活性。聚合物前药平台最近展示了 对高致死性和抗药性细菌肺部感染有很强的增强作用。这些 “药物玩家”疗法通过靶向特定的细胞储存库来改善肺部药物的活性。 具有高剂量和延长剂量分布的肺部。该吸入性平台以前可供感染患者使用 住院，以减少拥挤医院中患者的管理，并贡献关键的可分配 保护照料者和弱势群体所需的治疗和预防方式。这个 提案围绕4个具体目标展开：(1)将瑞美西韦和巴拉西替尼作为首选候选药物 利用肺巨噬细胞作为储存库来实现延长给药时间，以及针对 肺上皮病毒库。雷米西韦和巴拉西替尼前药单体将与 相应的药物玩家设计带有甘露糖和多肽靶向配体的肺泡巨噬细胞和 上皮室；(2)通过以下标准来表征和优化候选药物玩家 他们将药物加载到肺巨噬细胞和上皮细胞中，剂量时间延长。这将导致更好的 了解如何为未来的抗病毒开发优化肺部靶向策略。这个 将通过定量LC-MS药代动力学表征和安全性来研究其作用机制 使用肺部炎症反应评估进行表征；(3)评估和优化药物玩家的活性 用hACE2小鼠模型抗SARS-CoV-2。病毒载量和存活研究将被用来表征 并开发优化的游戏玩家和游戏玩家组合，这些组合在未来可以推广到 临床前发展。与目前的处方方法相比，毒品游戏玩家表现出更高的药物 加载，能够共同配制多种不同的药物用于综合治疗，以及个人定制的药物PK 最大限度地减少突发释放的配置文件。平台的模块化，以及规模化和快速制造 反应属性，将允许将其他药物作为组合进行不同的合并。这些有利的平台 属性促使该项目开发当前和未来的冠状病毒治疗产品的新曲目。

PROJECT SUMMARY/ABSTRACT The newly emerged SARS-CoV-2 coronavirus has demonstrated the deadly threat of pulmonary pathogens in an exposure-naïve world with no existing vaccines or therapeutics at the ready. The development of effective vaccines has provided key prophylactic products, but therapeutics remain important due to slow and incomplete world coverage, along with emergence of resistance variants. There is especially a need for polytherapy platforms that can be deployed in formats amenable to global settings, and need for platforms that can be rapidly developed against future pulmonary threats. This project aims to develop a versatile inhalable therapeutic platform against COVID-19 disease and future coronaviruses. It is designed for nebulizer and distributable inhalation devices to maximize drug activity in the lung. The polymeric prodrug platform has recently shown strong potentiating activity against highly lethal and antimicrobial-resistant bacterial lung infections. These “drugamer” therapeutics improve the activity of pulmonary drugs by targeting them to specific cell reservoirs in the lung with high and extended dosing profiles. The inhalable platform could be used by infected patients before hospitalization, to reduce administrations by patients in crowded hospitals, and contribute a key distributable therapeutic and prophylactic modality that is needed to protect caregivers and disadvantaged populations. The proposal is structured around 4 specific aims: (1) Develop remdesivir and baracitinib as first drugamer candidates that exploit the lung macrophage as a reservoir to achieve extended dosing, as well as targeted designs against lung epithelium viral reservoirs. Remdesivir and baracitinib prodrug monomers will be developed with corresponding drugamer designs with mannose and peptide targeting ligands for the alveolar macrophage and epithelial compartments, respectively; (2) Characterize and optimize the drugamer candidates by criteria of how they load drugs into the lung macrophage and epithelial cells with extended dosing times. This will lead to better understanding of how to optimize targeting strategies in the lung for future antiviral development. The mechanisms will be studied by using quantitative LC-MS pharmacokinetics characterization and safety characterization using lung inflammatory response assessments; (3) Assess and optimize drugamer activity against SARS-CoV-2 using the hACE2 mouse model. Viral load and survival studies will be used to characterize and develop optimized drugamer and drugamer combinations that could in the future be carried forward into preclinical development. Compared to current formulation approaches, the drugamers exhibit higher drug loading, the ability to co-formulate widely varying drugs for polytherapy, and individually tailorable drug PK profiles that minimize burst release. The modularity of the platform, together with scaled and rapid manufacturing response attributes, will allow diverse incorporation of other drugs as combinations. These favorable platform attributes motivate this project to develop a new repertoire of current and future coronavirus therapeutic products.