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Advancing the development of a novel class of small molecules for treating pan-coronavirus infections

推进治疗泛冠状病毒感染的新型小分子的开发

基本信息

批准号：
10672328
负责人：
Shirit Einav
金额：
$ 71.38万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-10 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10672328
关键词：
2019-nCoV Advanced Development Alphavirus Animal Model Antineoplastic Agents Antiviral Agents Binding Biochemistry Biological Assay Biological Markers COVID-19 COVID-19 outbreak COVID-19 treatment CRISPR interference Cells Chemicals Clinical Research Clinical Trials Coronavirus Coronavirus Infections Cultured Cells Data Set Dengue Dengue Virus Development Dimensions Drug Combinations Drug Kinetics Ebola Ebola virus Endosomes Erlotinib Excretory function GAK gene Genetic Genomics Growth Guide RNA Hamsters Human In Vitro Individual Industry Inflammation Inflammatory Inflammatory Response Integration Host Factors Investigational Drugs Laboratories Lead Life Cycle Stages Lung Measures Mediating Membrane Metabolism Modeling Molecular Molecular Target Molecular Virology Monitor Morbidity - disease rate Mus Organoids Pathway interactions Peripheral Blood Mononuclear Cell Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacology Study Phosphotransferases Production Property Proteomics RNA Viruses Readiness Regimen Reporting Research Resistance Resources Risk Rodent Model Role SARS-CoV-2 entry inhibitor SARS-CoV-2 infection SARS-CoV-2 inhibitor SARS-CoV-2 pathogenesis Safety Series Structure of parenchyma of lung Structure-Activity Relationship Study models Therapeutic Therapeutic Index Toxic effect Toxicology Translating Viral Viral Load result Viral Physiology Virus Virus Diseases Virus Replication Work absorption activity-based protein profiling analog chemical genetics combat cytokine design drug candidate drug development drug repurposing forest future outbreak future pandemic genome-wide in vivo inhibitor insight mortality novel off-label use pandemic coronavirus pharmacologic preclinical safety programs pyridine response side effect small molecule tissue injury tool trafficking treatment response virology virus host interaction

项目摘要

Abstract For the past decade, our laboratory has been studying the role of cellular kinases in intracellular trafficking of RNA viruses and as targets for broad-spectrum antivirals. Furthermore, we have provided a proof of concept for the potential feasibility of the host-targeted broad-spectrum antiviral approach by demonstrating that the inhibition of two cellular kinases, AAK1 and GAK, by novel or the approved anticancer drugs, sunitinib and erlotinib, protects mice from dengue and Ebola viruses with a high barrier to resistance. Since the therapeutic index (TI) of this drug combination is narrower for SARS-CoV-2 infection, here, we focus on an independent class of compounds, the isothiazolo[4,3-b]pyridine-based RMC-113 series, that emerged from our prior work, but does not inhibit AAK1 or GAK. We showed that RMC-113 and 25 related analogs have potent broad- spectrum antiviral activity with a high barrier to resistance. Excitingly, RMC-113 reduces SARS-CoV-2 titer to undetectable levels at non-toxic concentrations and binds PIKFYVE, a cell kinase that regulates endosomal trafficking. We hypothesize that RMC-113 analogs inhibit both multiple distinct steps in the SARS-CoV-2 life cycle and the inflammatory response to this virus, in part by targeting PIKFYVE, thereby offering attractive and safe candidate inhibitors to combat SARS-CoV-2, other pandemic coronaviruses and other emerging viruses. In Aim 1, we will use a multi-dimensional medicinal chemistry approach to optimize the TI and PK profile of lead RMC-113 analogs and define their in vitro therapeutic potential as broad anticoronavirus inhibitors. Aim 2 will determine the effect of prioritized analogs and apilimod, a repurposed drug candidate for COVID-19 that inhibits PIKFYVE, on viral replication, cytokine response and tissue injury in organoids derived from excised normal lung tissue supplemented with PBMCs from 20 human donors and in two rodent models. Aim 3 will generate ADME-toxicity and safety pharmacology datasets to select pre-IND candidates. In Aim 4, we will probe the mechanism of antiviral action of RMC-113. We will validate PIKFYVE as a candidate target and use an unbiased CRISPRi screen to identify RMC-113’s target(s) and profile its chemical-genetic landscape. In parallel, we will design a clickable RMC-113 probe to confirm the molecular target via activity-based protein profiling and to monitor target engagement. Lastly, we will probe functional relevance and specific roles of PIKFYVE and other candidates emerging via these approaches in SARS-CoV-2 infection, and validate them as the molecular target(s) mediating the antiviral effect. The predicted immediate impact is that this project will provide insight into the therapeutic potential and MOA of apilimod, a repurposed drug candidate (beyond the reported effect on viral entry), and will establish a unique human lung organoid model for studying SARS-CoV- 2 pathogenesis and response to treatment under more natural conditions. In the longer term, successful completion of our study will deliver a drug-like small molecule candidate designed to protect against resurge of COVID-19 and to provide readiness for future outbreaks with coronaviruses and other emerging viruses.

抽象的在过去的十年中，我们的实验室一直在研究细胞激酶在细胞内转运中的作用 RNA 病毒并作为广谱抗病毒药物的靶点。此外，我们还提供了概念证明通过证明针对宿主的广谱抗病毒方法的潜在可行性新型或已批准的抗癌药物舒尼替尼和 AAK1 和 GAK 抑制两种细胞激酶厄洛替尼可保护小鼠免受登革热和埃博拉病毒的侵害，并具有很高的抵抗力。自从治疗该药物组合的指数（TI）对于 SARS-CoV-2 感染较窄，在这里，我们重点关注一个独立的一类化合物，基于异噻唑并[4,3-b]吡啶的RMC-113系列，是我们之前工作中出现的，但不抑制 AAK1 或 GAK。我们证明 RMC-113 和 25 种相关类似物具有有效的广泛作用具有高耐药屏障的谱抗病毒活性。令人兴奋的是，RMC-113 将 SARS-CoV-2 滴度降低至在无毒浓度下达到不可检测的水平，并结合 PIKFYVE（一种调节内体的细胞激酶）贩运。我们假设 RMC-113 类似物抑制 SARS-CoV-2 生命中的多个不同步骤周期和对该病毒的炎症反应，部分是通过靶向 PIKFYVE，从而提供有吸引力和对抗 SARS-CoV-2、其他大流行冠状病毒和其他新出现病毒的安全候选抑制剂。在目标 1 中，我们将使用多维药物化学方法来优化 TI 和 PK 特征领先的 RMC-113 类似物并确定其作为广泛抗冠状病毒抑制剂的体外治疗潜力。目标2 将确定优先类似物和阿匹莫德的效果，阿匹莫德是一种针对 COVID-19 的重新调整用途的候选药物，抑制 PIKFYVE 对切除的类器官中的病毒复制、细胞因子反应和组织损伤的影响正常肺组织补充了来自 20 名人类捐赠者和两种啮齿动物模型的 PBMC。目标3将生成 ADME 毒性和安全性药理学数据集以选择 IND 前候选药物。在目标 4 中，我们将探讨RMC-113的抗病毒作用机制。我们将验证 PIKFYVE 作为候选目标并使用一种公正的 CRISPRi 筛选，用于识别 RMC-113 的靶标并分析其化学遗传图谱。在同时，我们将设计一个可点击的 RMC-113 探针，通过基于活性的蛋白质来确认分子靶标分析并监控目标参与度。最后，我们将探讨功能相关性和具体作用 PIKFYVE 和通过这些方法在 SARS-CoV-2 感染中出现的其他候选药物，并将其验证为介导抗病毒作用的分子靶标。预计该项目的直接影响是深入了解阿匹莫德的治疗潜力和作用机制，阿匹莫德是一种重新调整用途的候选药物（超出了报道了对病毒进入的影响），并将建立一个独特的人肺类器官模型来研究 SARS-CoV- 2 更自然条件下的发病机制和治疗反应。从长远来看，成功我们的研究完成后将提供一种类似药物的小分子候选药物，旨在防止病毒再次出现 COVID-19 并为未来冠状病毒和其他新兴病毒的爆发做好准备。