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） 病毒蛋白NSP7和NSP8的复合物进行必不可少的RNA合成反应，是一个吸引人的，并且 抗病毒药物的验证靶标。迄今为止，抑制RDRP活性的核苷类似物显示出有望 COVID-19治疗。其中包括Remdesivir（RDV），腺苷模拟GS-441524的前药和 首次通过FDA批准的抗病毒治疗COVID-19。最近3阶段的莫纳皮拉维尔（Molnupiravir）临床数据 β-D-N4-羟基辛丁定（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，限制其门诊的使用，而Molnupiravir则是口服的 管理但需要高剂量。此外，最先进的核苷抑制剂没有 专门用于治疗冠状病毒感染。在这里，我们提出了三种平行的方法来提供 优化的新药物以靶向SARS-COV-2 RDRP并治疗冠状病毒感染。在第一种方法中， 我们以非人类隐私的有希望的初步数据为基础 口服暴露与RDV，以便在门诊环境中使用口服给药 日给药方案。我们的第二种方法旨在识别和优化针对的新型核苷类似物 SARS-COV-2 RDRP。这种方法的关键将是筛选包括167个小说的核能库 在空气中分化的人支气管上皮细胞中对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评估来筛选一个新颖的结构库 多样的“功能化碎片”和第二个半胱氨酸和赖氨酸反应化合物的文库 鉴定变构抑制剂。有希望的RDRP抑制剂将通过测试测试泛氧化病毒电位 对抗SARS-COV，MERS-COV和季节性冠状病毒。因为RDRP共享组成的结构，所以 广谱活动是可能的，并且是可取的。因此，我们将评估最高的RDRP抑制剂 该项目以及第5和6项目将重点介绍arbovirus和出血性发烧病毒 建立的生化RDRP分析，用于一系列新兴病毒。这些测定将提供机械 深入了解广谱活动的基础。并行，深层的方法将用于定义 MOA在感染的细胞和动物中。对于这些研究，复合进展将由迭代驱动 药物化学核心（核心B）的优化，针对冠状病毒复制测定法的生物学分析 在HTS核心（核心A），ADME，PK和毒理学分析中，来自药理学核心（Core C），动物 功效研究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研究 使用结构和建模核心（核心E）发现泛活动冠状病毒临床前 候选人具有优于RDV和Molnupiravir的候选者。