Inhibitors of SARS-CoV-2 Polymerase

SARS-CoV-2 聚合酶抑制剂

• 批准号: 10514325
• 负责人: Christopher F Basler
• 金额: $ 435.32万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 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/10514325
• 关键词: 2019-nCoV; Adenosine; Air; Animal Model; Animals; Antiviral Agents; Arboviruses; Area Under Curve; Biochemical; Biological; Biological Assay; Biological Availability; COVID-19 assay; COVID-19 treatment; Cell Differentiation process; Cells; Chemicals; Clinical Data; Collaborations; Complement; Complex; Coronavirus; Coronavirus Infections; Cysteine; Data; Development; Disease Progression; Dose; Drug Kinetics; Environment; Enzymes; Escape Mutant; FDA Emergency Use Authorization; FDA approved; Family; Formulation; Frequencies; GS-441524; Human; Intravenous; Lead; Libraries; Liquid substance; Lysine; Macaca mulatta; Medicine; Methods; Middle East Respiratory Syndrome Coronavirus; Modification; Molecular; Nonstructural Protein; Nucleosides; Oral; Oral Administration; Organoids; Orthobunyavirus; Outpatients; Parents; Pharmaceutical Chemistry; Pharmacology; Phase; Polymerase; Prodrugs; Proteins; Proteomics; RNA Polymerase Inhibitor; RNA chemical synthesis; RNA-Directed RNA Polymerase; Reaction; Regimen; Resistance; Rodent; SARS coronavirus; SARS-CoV-2 inhibitor; Secondary to; Series; Structural Models; Structure; Suspensions; Technology; Testing; Toxicology; Viral Hemorrhagic Fevers; Viral Proteins; Virus; Virus Replication; analog; animal efficacy; aqueous; base; biological systems; bronchial epithelium; deep sequencing; drug discovery; efficacy study; hemorrhagic fever virus; improved; indexing; inhibitor; insight; molnupiravir; nonhuman primate; novel; novel therapeutics; nucleoside analog; nucleoside inhibitor; pandemic preparedness; pre-clinical; remdesivir; screening; seasonal coronavirus; small molecule; small molecule inhibitor; tripolyphosphate; viral RNA

SUMMARY The SARS-CoV-2 RNA-dependent RNA polymerase (RDRP), non-structural protein 12 (NSP12), which in complex with viral proteins nsp7 and nsp8 carries out essential RNA synthesis reactions, is an attractive and well-validated target for antivirals. To date, nucleoside analogs that inhibit RDRP activity show promise as COVID-19 treatments. Among these is remdesivir (RDV), a prodrug of the adenosine analog GS-441524 and the first FDA-approved antiviral for the treatment of COVID-19. Recent phase 3 clinical data for molnupiravir, a prodrug of β-D-N4-hydroxycytidine (NHC), has encouraged Merck to seek Emergency Authorization Use. Whereas RDV suffers from lack of oral bioavailability, limiting its outpatient use, molnupiravir is orally administered but requires frequent high doses. Further, none of the most advanced nucleoside inhibitors were developed specifically to treat coronavirus infections. Here, we propose three parallel approaches to provide novel drugs optimized to target the SARS-CoV-2 RDRP and treat coronavirus infections. In the first approach, we build on promising preliminary data in non-human primates as we aim to develop a prodrug with improved oral exposure vs. RDV so as to enable oral administration for use in the outpatient setting, preferably a once a day dosing regimen. Our second approach seeks to identify and optimize novel nucleoside analogs against SARS-CoV-2 RDRP. Key to this approach will be the screening of a nucleoside library that includes 167 novel analogs for activity against SARS-CoV-2 in human bronchial epithelial cells differentiated in an air-liquid interface. Third, we will use a cell-based assay of SARS-CoV-2 RDRP to screen a novel library of structurally diverse “fully functionalized fragments” and a second library of cysteine- and lysine-reactive compounds to identify allosteric inhibitors. Promising RDRP inhibitors will be tested for pan-coronavirus potential by testing against SARS-CoV, MERS-CoV and seasonal coronaviruses. Because RDRPs share conserved structures, broad-spectrum activity is possible and would be desirable. Therefore, we will evaluate top RDRP inhibitors from this Project and from Projects 5 and 6, which will focus on arboviruses and hemorrhagic fever viruses, in established biochemical RDRP assays for a panel of emerging viruses. These assays will provide mechanistic insight into the basis for broad-spectrum activity. In parallel, deep-sequencing approaches will be used to define MOA in infected cells and animals. For these studies, compound progression will be driven by iterative optimization by the Medicinal Chemistry Core (Core B), biological profiling against coronavirus replication assays in the HTS Core (Core A), ADME, PK and toxicology profiling from the Pharmacology Core (Core C), animal efficacy studies in collaboration with the Organoid and Animal Model Core (Core D), and structure-based drug discovery with the Structural and Modeling Core (Core E) to deliver a pan-active coronavirus preclinical candidate with a profile superior to RDV and molnupiravir.

概括 SARS-CoV-2 RNA 依赖性 RNA 聚合酶 (RDRP)、非结构蛋白 12 (NSP12)， 与病毒蛋白 nsp7 和 nsp8 的复合物进行必要的 RNA 合成反应，是一种有吸引力的且 经充分验证的抗病毒药物靶点。迄今为止，抑制 RDRP 活性的核苷类似物显示出以下前景： COVID-19 治疗。其中包括瑞德西韦 (RDV)，它是腺苷类似物 GS-441524 的前药和 第一种 FDA 批准的用于治疗 COVID-19 的抗病毒药物。 molnupiravir 的最新 3 期临床数据 β-D-N4-羟基胞苷（NHC）的前药，鼓励默克寻求紧急授权使用。 RDV 缺乏口服生物利用度，限制了其门诊使用，而莫努匹拉韦是口服药物 施用但需要频繁的高剂量。此外，没有一种最先进的核苷抑制剂是 专门开发用于治疗冠状病毒感染。在这里，我们提出了三种并行方法来提供 针对 SARS-CoV-2 RDRP 并治疗冠状病毒感染进行优化的新型药物。在第一种方法中， 我们建立在非人类灵长类动物中有希望的初步数据的基础上，因为我们的目标是开发一种具有改进的前药 口服暴露与 RDV 的比较，以便能够在门诊环境中口服给药，最好是一次一次 日给药方案。我们的第二种方法旨在识别和优化新型核苷类似物 SARS-CoV-2 RDRP。该方法的关键是筛选包含 167 个新颖的核苷库 在空气-液体中分化的人支气管上皮细胞中具有抗 SARS-CoV-2 活性的类似物 界面。第三，我们将使用基于细胞的 SARS-CoV-2 RDRP 检测来筛选一个新的结构文库。 多样化的“全功能化片段”和第二个半胱氨酸和赖氨酸反应性化合物库 识别变构抑制剂。有前途的 RDRP 抑制剂将通过测试来测试泛冠状病毒潜力 对抗 SARS-CoV、MERS-CoV 和季节性冠状病毒。由于 RDRP 具有保守的结构， 广泛的活动是可能的，也是可取的。因此，我们将评估来自以下国家的顶级 RDRP 抑制剂： 该项目以及项目 5 和 6 将重点关注虫媒病毒和出血热病毒， 建立了针对一组新出现病毒的生化 RDRP 检测。这些测定将提供机械 深入了解广谱活动的基础。同时，深度测序方法将用于定义 受感染细胞和动物中的 MOA。对于这些研究，复合进展将由迭代驱动 通过药物化学核心（核心 B）进行优化，针对冠状病毒复制分析进行生物分析 在 HTS 核心（核心 A）、药理学核心（核心 C）的 ADME、PK 和毒理学分析中，动物 与类器官和动物模型核心（核心 D）以及基于结构的药物合作进行功效研究 与结构和建模核心（核心 E）进行发现，以提供泛活性冠状病毒临床前研究 候选药物的性能优于 RDV 和 molnupiravir。