Inhalation Therapy Platform for Coronavirus Infection Treatment

项目总结/摘要 新出现的SARS-CoV-2冠状病毒已经证明了肺部病原体的致命威胁， 这是一个没有现成疫苗或治疗方法的天真世界。制定有效 疫苗提供了关键的预防性产品，但由于缓慢和不完全， 沿着耐药变异体的出现。特别需要综合疗法 能够以符合全球环境的格式部署的平台，以及能够迅速 针对未来肺部威胁的发展。该项目旨在开发一种多功能的可吸入治疗剂， 我们是对抗COVID-19疾病和未来冠状病毒的平台。它是专为雾化器和分布式 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显示 对高致死性和抗微生物剂抗性细菌肺部感染的强增强活性。这些 “drugamer”疗法通过将肺部药物靶向特定的细胞库来改善肺部药物的活性， 肺具有高剂量和延长剂量曲线。可吸入平台可供受感染的患者使用， 住院，以减少病人在拥挤的医院的管理，并提供一个关键的分配 这是保护护理人员和弱势群体所需的治疗和预防方式。的 该提案围绕4个具体目标构建：（1）开发remdesivir和baracitinib作为首个药物开发候选药物 利用肺巨噬细胞作为储库来实现延长剂量，以及针对 肺上皮病毒储库。Remdesivir和baracitinib前药单体将与 具有针对肺泡巨噬细胞的甘露糖和肽靶向配体的相应药物分子设计， （2）通过以下标准来表征和优化drugamer候选物： 它们以延长的给药时间将药物加载到肺巨噬细胞和上皮细胞中。这将导致更好的 了解如何优化肺部靶向策略，以用于未来的抗病毒开发。的 将通过使用定量LC-MS药代动力学表征和安全性研究机制 使用肺部炎症反应评估表征;（3）评估和优化药物活性 使用hACE 2小鼠模型对抗SARS-CoV-2。将使用病毒载量和生存期研究来表征 并开发优化的drugamer和drugamer组合，在未来可以进行到 临床前开发。与目前的制剂方法相比，druggamers表现出更高的药物活性。 载量，共同配制多种药物用于多种治疗的能力，以及可单独定制的药物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 响应属性，将允许作为组合的其它药物的不同掺入。这些有利的平台 这些特性促使该项目开发一种新的现有和未来的冠状病毒治疗产品。

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.