Inhalation Therapy Platform for Coronavirus Infection Treatment

治疗冠状病毒感染的吸入治疗平台

• 批准号: 10687201
• 负责人: Patrick S. Stayton
• 金额: $ 66.26万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687201
• 关键词: 2019-nCoV; Alveolar Macrophages; Alveolus; Anti-Inflammatory Agents; Antibiotics; Antimicrobial Resistance; Antiviral Agents; Azithromycin; Biological Availability; Biomedical Engineering; Burkholderia pseudomallei; COVID-19; COVID-19 outbreak; COVID-19 pandemic; COVID-19 therapeutics; Caregivers; Cells; Cessation of life; Clinical; Coronavirus; Coronavirus Infections; Crowding; Development; Diffusion; Disadvantaged; Disease; Disease model; Disparity population; Dose; Doxycycline; Drug Combinations; Drug Kinetics; Drug Targeting; Drug resistance; Effectiveness; Enzymes; Epithelial Cells; Epithelium; Evolution; Exhibits; Formulation; Future; Gap Junctions; Histologic; Hospitalization; Hospitals; Human; Individual; Inflammatory Response; Inhalation; Inhalation Device; Inhalation Drug Administration; Inhalation Therapy; Intensive Care; Lead; Leadership; Life; Ligands; Lung; Lung infections; Macrophage; Mannose; Mediating; Melioidosis; Methods; Modality; Modeling; Nebulizer; Oral; Organ; Patients; Peptides; Pharmaceutical Preparations; Polymers; Population; Positioning Attribute; Predisposition; Procedures; Prodrugs; Property; Pulmonology; Research Personnel; Resistance; Resource-limited setting; Rodent Diseases; Rodent Model; SARS-CoV-2 variant; Safety; Schedule; Solubility; Source; Structure; Testing; Therapeutic; Time; Toxic effect; Tularemia; Vaccination; Vaccines; Variant; Viral; Viral Load result; Viral reservoir; Work; alveolar epithelium; antiviral drug development; bacterial resistance; clinical development; coronavirus therapeutics; density; design; drug candidate; drug isolation; experience; future pandemic; improved; liquid chromatography mass spectrometry; lung pathogen; manufacture; manufacturing scale-up; monomer; mouse model; novel vaccines; pandemic potential; pathogen; pharmacokinetics and pharmacodynamics; polymerization; preclinical development; prophylactic; pulmonary agents; remdesivir; response; unvaccinated; uptake; viral entry inhibitor

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.

项目概要/摘要 新出现的 SARS-CoV-2 冠状病毒已证明肺部病原体的致命威胁 一个未经暴露的世界，没有现成的疫苗或治疗方法。发展有效的 疫苗提供了关键的预防产品，但由于进展缓慢且不完整，治疗方法仍然很重要 世界范围内的报道，以及耐药变种的出现。尤其需要多疗法 可以以适合全球环境的格式部署的平台，并且需要可以快速部署的平台 针对未来肺部威胁而开发的。该项目旨在开发一种多功能吸入式治疗药物 针对 COVID-19 疾病和未来冠状病毒的平台。它专为雾化器和分布式 吸入装置可最大限度地提高肺部药物活性。聚合物前药平台最近显示 对高致命性和抗菌药物耐药性细菌肺部感染具有强大的增强活性。这些 “药物玩家”疗法通过将肺部药物靶向特定的细胞储存库来提高肺部药物的活性。 肺部具有高剂量和延长的剂量曲线。吸入式平台之前就可以被感染患者使用 住院治疗，以减少患者在拥挤的医院接受治疗，并贡献一个关键的可分配资源 保护护理人员和弱势群体所需的治疗和预防方式。这 该提案围绕 4 个具体目标构建：(1) 开发瑞德西韦和巴拉替尼作为首批候选药物 利用肺巨噬细胞作为储存库来实现延长给药，以及针对 肺上皮病毒储存库。瑞德西韦和巴拉替尼前药单体将与 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和 上皮区室，分别； (2) 通过以下标准表征和优化候选药物分子： 他们将药物加载到肺巨噬细胞和上皮细胞中，并延长给药时间。这将带来更好的 了解如何优化肺部靶向策略以促进未来抗病毒药物的开发。这 将使用定量 LC-MS 药代动力学表征和安全性来研究机制 使用肺部炎症反应评估进行表征； (3) 评估和优化药物活性 使用 hACE2 小鼠模型对抗 SARS-CoV-2。病毒载量和生存研究将用于表征 并开发优化的药物分子和药物分子组合，将来可以将其推广到 临床前开发。与目前的制剂方法相比，药物分子表现出更高的药物 负荷、共同配制多种药物用于多疗法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，将允许多种其他药物作为组合结合。这些有利平台 这些特性促使该项目开发当前和未来的冠状病毒治疗产品的新品种。