Project 1 – Development of Orally Bioavailable beta-CoV Inhibitors

项目摘要-项目1 COVID-19疫情对健康及社会经济造成前所未有的影响。尽管快速 疫苗的产生、疫苗接种的犹豫、关注的病毒变体（VOC）的出现以及突破 病例推动了持续的社区传播，为下一步的发展创造了最大的紧迫性， 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 建立高的组织暴露，以最大限度地提高急性RNA病毒感染中药物干预的益处。 诊断能力的突破性扩展与有效的接触者追踪相结合， 基础设施，以确定SARS-CoV-2的传播之前，具体的临床症状发作。口服生物利用度 和高耐受性在我们看来是有效地满足门诊病人需要的关键药物特性。 直接作用的抗病毒药物似乎最适合于将联合收割机的高效性与适当的安全性特征相结合。 我们先前已经鉴定了口服有效的核苷类似物抑制剂EIDD-2801/莫努匹拉韦， 确立了药物抑制SARS-CoV-2传播至未经治疗的接触者的概念验证 使用雪貂传播模型。这个AC/DC项目的首要目标是利用我们展示的 在开发适用的治疗方法和降低风险的机制和结构上不同的专业知识， 莫努匹拉韦的伴随药物和至少一种正式开发阶段的独立替代药物。在 初步研究，我们已经确定了一种新的尿苷类似物，显示出出色的口服药代动力学（PK） 在不同物种中的特性，在培养细胞和原代人气道中的广谱抗病毒活性 上皮类器官，通过诱导延迟聚合酶链终止发挥作用，口服有效 针对SARS-CoV-2、VOC和其他几种可能大流行的病毒病原体。扩大我们的抗新冠病毒 投资组合，我们将在多管齐下的方法同时推进早期腺苷类似物抗CoV hit和，开创了重组SARS-CoV-2报告病毒技术和小型化的高， 高通量筛选（HTS）协议，利用我们建立的高通量筛选机制， 生物安全高温超导设施为了准备正式的开发，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 （aim1）。将通过直接和正交试验验证HTS中的非核苷抗CoV命中候选物 反筛选、病毒靶点鉴定、适应症谱和机制分析（目标2）。证实 核苷类似物和非核苷CoV抑制剂将在迭代轮中进行合成优化， 通过抗病毒效力、PK特性、耐受性和对分子对接姿势的洞察（目的3）。新兴 将使用SARS-CoV-2感染的雪貂和侏儒仓鼠模型， 评估化合物经历的VOC，通过动态PK特征的接口探索给药模式 在人类类器官中的性能，以及在非人灵长类动物COVID-19模型中验证的结果（目的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).