Inhibitors of SARS-CoV-2 Polymerase

SARS-CoV-2 聚合酶抑制剂

基本信息

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
项目类别：
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

项目摘要

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迄今为止，抑制 RDRP 活性的核苷类似物显示出良好的抗病毒靶点。其中包括瑞德西韦 (RDV)，它是腺苷类似物 GS-441524 的前药。首个 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。在全球范围内，RDV 缺乏口服生物利用度，限制了其门诊使用，molnupiravir 是口服药物但需要频繁的高剂量。此外，没有一种最先进的核苷抑制剂被使用。在这里，我们提出了三种并行的方法来提供专门治疗冠状病毒感染的方法。针对 SARS-CoV-2 RDRP 进行优化并治疗冠状病毒感染的新颖方法在第一种方法中，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 活性的类似物第三，我们将使用基于细胞的 SARS-CoV-2 RDRP 检测来筛选新的结构文库。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通过测试来确定有前景的 RDRP 抑制剂的泛冠状病毒潜力。由于 RDRP 具有保守的结构，因此能够抵抗 SARS-CoV、MERS-CoV 和季节性冠状病毒。广谱活性是可能的并且是可取的，因此，我们将评估顶级 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，针对一组新出现的病毒建立了生化 RDRP 检测，这些检测将提供机制。同时，深度测序方法将用于定义广谱活动的基础。对于这些研究，受感染细胞和动物中的 MOA 将通过迭代驱动。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。