Project 1 – Development of Orally Bioavailable beta-CoV Inhibitors

项目摘要-项目1 新冠肺炎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、疫苗接种的犹豫不决、病毒变种的出现(VOC)和突破 病例推动了持续的社区传播，为下一步的发展创造了极大的紧迫性 新一代的抗病毒药物。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急性RNA病毒感染的好处。 突破性地扩展了诊断能力，并结合了有效的接触者追踪 在出现特定临床症状之前识别SARS-CoV-2传播的基础设施。口服生物利用度 在我们看来，高耐受性是有效满足门诊患者需求的关键药物特性。 直接作用的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。 我们之前已经鉴定了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 使用雪貂传播模型。此AC/DC项目的首要目标是利用我们演示的 在开发适用的治疗方法和降低风险方面的专业知识在机械和结构上截然不同 Molnupiravir的配伍药物和至少一种正式开发阶段的独立替代品。在……里面 在试点研究中，我们发现了一种新的尿苷类似物，它表现出出色的口服药代动力学(PK)。 不同物种的特性、培养细胞和原代人呼吸道的广谱抗病毒活性 类上皮器，通过诱导延迟的聚合酶链终止起作用，口服有效。 对抗SARS-CoV-2、VOC和其他几种具有大流行潜力的病毒病原体。扩大我们的反伪装 我们将多管齐下，同时推进早期腺苷类似物抗冠状病毒 Hit和，开创了重组SARS-CoV-2报告病毒技术和微型化的高- 吞吐量筛查(HTS)协议，利用我们建立的高性能 生物遏制HTS设施。为了为正式开发做准备，核苷模拟课程将是 遵循完整的行为表征、阻力分析和脱靶效应评估机制 (目标1)。来自HTS的非核苷抗冠状病毒HIT候选将通过直接和正交验证 反筛选、病毒靶标识别、指示谱和机械分析(目标2)。确认 核苷类似物和非核苷冠状病毒抑制剂将在迭代回合中进行综合优化，驱动 通过抗病毒效力、PK特性、耐受性和对分子对接姿势的洞察(目标3)。新兴 使用SARS-CoV-2感染的雪貂和矮小仓鼠模型将降低铅的风险，发病机制 评估化合物经验的VOC，通过动态PK曲线的接口探索给药范例 在人类有机体中的表现，以及在非人类灵长类动物新冠肺炎模型中验证的结果(目标4)。

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).