Project 1 – Development of Orally Bioavailable beta-CoV Inhibitors

项目 1 — 口服生物可利用的 β-CoV 抑制剂的开发

• 批准号: 10513942
• 负责人: Richard K. Plemper
• 金额: $ 413.93万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513942
• 关键词: 2019-nCoV; 3-Dimensional; Acute; Acute Lung Injury; Address; Adenosine; Advanced Development; Animal Model; Antiviral Agents; Biochemical; Biological Assay; Biological Availability; COVID-19; COVID-19 pandemic; Cell Culture Techniques; Chemicals; Clinical; Companions; Contact Tracing; Containment; Coronavirus; Cryoelectron Microscopy; Cultured Cells; Development; Diagnostic; Disease; Docking; Dose; Drug Kinetics; Drug Screening; Drug or chemical Tissue Distribution; Dwarfism; Eligibility Determination; Exposure to; Failure; Family; Ferrets; Generations; Goals; Hamsters; Health; Human; Infection; Infrastructure; Intervention; Joints; Lead; Measurement; Middle East Respiratory Syndrome; Mission; Modeling; Molecular; Molecular Mechanisms of Action; Oral; Organoids; Outpatients; Paramyxovirus; Pathogenesis; Pathogenicity; Performance; Pharmaceutical Preparations; Pharmacology; Physiological; Pilot Projects; Polymerase; Property; RNA Virus Infections; RNA Viruses; Recombinants; Reporter; Resistance; Resistance profile; Risk; Safety; Severe Acute Respiratory Syndrome; Specificity; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Time; Tissues; Triage; Uridine; Vaccines; Validation; Viral; Virus; Work; airway epithelium; analog; animal efficacy; anti-viral efficacy; antiviral nucleoside analog; betacoronavirus; clinical application; clinical candidate; community transmission; coronavirus therapeutics; counterscreen; cytotoxicity; design; drug development; experience; flu; high throughput screening; human coronavirus; in vivo; in vivo imaging; influenzavirus; inhibitor; insight; lead candidate; miniaturize; molnupiravir; next generation; nonhuman primate; novel; nucleoside analog; pandemic disease; pathogen; pathogenic virus; pharmacophore; programs; reconstruction; socioeconomics; therapeutic candidate; transmission process; vaccine hesitancy; variants of concern

Project Summary – Project 1 The COVID-19 pandemic is exerting an unprecedented health and socioeconomic impact. Despite the rapid generation of vaccines, vaccination hesitancy, emergence of viral variants of concern (VOC), and breakthrough cases have fueled continued community transmission, creating utmost urgency for the development of next- generation antiviral drugs. Typically narrow therapeutic windows define a clear directive to treat early and rapidly build high tissue exposure to maximize the benefit of pharmacological intervention in acute RNA virus infections. Groundbreaking expansion of diagnostic capacity combined with efficient contact tracing have established infrastructure to identify SARS-CoV-2 transmission before the onset of specific clinical signs. Oral bioavailability and high tolerability are in our view key drug properties to efficiently serve the needs of an outpatient group. Direct-acting antivirals appear to be best suited to combine high potency with an appropriate safety profile. We have previously identified the orally efficacious nucleoside analog inhibitor EIDD-2801/molnupiravir and established proof-of-concept for pharmacological suppression of SARS-CoV-2 spread to untreated contacts using the ferret transmission model. It is the overarching goal of this AC/DC project to harness our demonstrated expertise in the development of applicable therapeutics and de-risk a mechanistically and structurally distinct companion drug to molnupiravir and at least one independent alternative to the stage of formal development. In pilot studies, we have identified a novel uridine analog that shows outstanding oral pharmacokinetic (PK) properties in different species, broad-spectrum antiviral activity in cultured cells and primary human airway epithelium organoids, acts through induction of delayed polymerase chain termination, and is orally efficacious against SARS-CoV-2, VOC, and several other viral pathogens of pandemic potential. To broaden our anti-CoV portfolio, we will in a multi-pronged approach simultaneously advance an early-stage adenosine analog anti-CoV hit and, having pioneered recombinant SARS-CoV-2 reporter virus technology and miniaturized a high- throughput screening (HTS) protocol, launch an anti-SARS-CoV-2 campaign using our established high- biocontainment HTS facilities. To prepare for formal development, the nucleoside analog classes will be subjected to full mechanism of action characterization, resistance profiling, and assessment of off-target effects (aim1). Non-nucleoside anti-CoV hit candidates from HTS will be validated through direct and orthogonal counterscreens, viral target identification, and indication spectrum and mechanistic profiling (aim 2). Confirmed nucleoside analog and non-nucleoside CoV inhibitors will be synthetically optimized in iterative rounds, driven by antiviral potency, PK properties, tolerability, and insight into the molecular docking pose (aim 3). Emerging leads will be de-risked using the ferret and dwarf hamster models of SARS-CoV-2 infection, pathogenesis of compound-experienced VOC assessed, dosing paradigms explored through interfacing of dynamic PK profiles with performance in human organoids, and results validated in a non-human primate COVID-19 model (aim 4).

项目概要 – 项目 1 COVID-19 大流行正在对健康和社会经济产生前所未有的影响。尽管速度很快 疫苗的产生、疫苗接种犹豫、关注病毒变种 (VOC) 的出现以及突破 病例推动了持续的社区传播，为制定下一步措施创造了极大的紧迫性 一代抗病毒药物。通常狭窄的治疗窗口定义了早期和快速治疗的明确指示 建立高组织暴露，以最大限度地发挥药物干预对急性 RNA 病毒感染的益处。 诊断能力的突破性扩展与高效的接触者追踪相结合 在特定临床症状出现之前识别 SARS-CoV-2 传播的基础设施。口服生物利用度 我们认为，高耐受性是有效满足门诊群体需求的关键药物特性。 直接作用抗病毒药物似乎最适合将高效力与适当的安全性结合起来。 我们之前已经鉴定出口服有效的核苷类似物抑制剂 EIDD-2801/molnupiravir 和 建立了药物抑制 SARS-CoV-2 向未经治疗的接触者传播的概念验证 使用雪貂传输模型。该 AC/DC 项目的总体目标是利用我们已证明的 开发适用疗法的专业知识，并降低机械和结构上不同的风险 molnupiravir 的伴随药物和至少一种正式开发阶段的独立替代药物。在 通过初步研究，我们发现了一种新型尿苷类似物，它具有出色的口服药代动力学 (PK) 不同物种的特性、培养细胞和人类初级气道的广谱抗病毒活性 上皮类器官，通过诱导延迟聚合酶链终止起作用，口服有效 针对 SARS-CoV-2、VOC 和其他几种具有大流行潜力的病毒病原体。扩大我们的抗冠状病毒 产品组合中，我们将多管齐下，同时推进早期腺苷类似物抗冠状病毒 并开创了重组 SARS-CoV-2 报告病毒技术并将高 通量筛选 (HTS) 方案，利用我们已建立的高 生物防护高温超导设施。为了准备正式开发，核苷类似物类将 进行完整的作用机制表征、耐药性分析和脱靶效应评估 （目标1）。 HTS 的非核苷抗冠状病毒候选药物将通过直接和正交验证 反筛选、病毒目标识别、指示谱和机制分析（目标 2）。确认的 核苷类似物和非核苷冠状病毒抑制剂将在迭代中进行综合优化，驱动 通过抗病毒效力、PK 特性、耐受性和对分子对接姿势的深入了解（目标 3）。新兴 使用 SARS-CoV-2 感染的雪貂和侏儒仓鼠模型来降低潜在风险， 化合物经历过的 VOC 评估，通过动态 PK 配置文件的接口探索剂量范式 具有在人类类器官中的表现，并在非人类灵长类动物 COVID-19 模型中验证了结果（目标 4）。