Development of outpatient antiviral cocktails against SARS-CoV-2 and other potential pandemic RNA viruses.

开发针对 SARS-CoV-2 和其他潜在大流行性 RNA 病毒的门诊抗病毒鸡尾酒。

• 批准号: 10514264
• 负责人: JEFFREY S GLENN
• 金额: $ 6905.87万
• 依托单位: STANFORD UNIVERSITY
• 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/10514264
• 关键词: 2019-nCoV; Achievement; Ambulatory Care; Antisense Oligonucleotides; Antiviral Agents; Antiviral Therapy; COVID-19 treatment; Clinic; Clinical; Collection; Containment; Coronavirus; Data Set; Development; Drug Combinations; Drug resistance; Ensure; Exonuclease; Formulation; Funding; Future; Genome; Goals; Individual; Industry; Lead; Life Cycle Stages; Ligands; Membrane; Mentors; Methods; Modality; Mutagenesis; Mutation; Nucleic Acids; Outpatients; Peptides; Peptoids; Pharmaceutical Preparations; Program Research Project Grants; Proteins; RNA; RNA Viruses; RNA replication; Research Personnel; Resistance; Resources; Ribonucleosides; Role; SARS-CoV-2 inhibitor; SARS-CoV-2 protease; Structure; Talents; Testing; Translating; Translations; Viral; Viral Genome; Viral Proteins; Virus; analog; anti-viral efficacy; antisense nucleic acid; circular RNA; combat; drug development; drug discovery; improved; in vivo; industry partner; inhibitor; innovation; insight; lead optimization; locked nucleic acid; novel; novel strategies; nucleic acid-based therapeutics; pandemic disease; preclinical development; programs; small molecule; small molecule inhibitor; small molecule therapeutics; structural biology; therapeutic protein; therapeutic target; translational pipeline; viral RNA

ABSTRACT: The overall platform and objective of the Stanford AViDD Center, “SyneRx,” is to develop outpatient antiviral cocktails against SARS-CoV-2 and other potential pandemic RNA viruses. Thus, the goal of each of our 7 Projects is to develop towards the clinic a novel direct-acting antiviral (DAA) with a distinct mechanism of action, so that they can be used alone and in combination with other agents—providing additive, and ideally synergistic antiviral activity. To maximize the achievement of this goal, we seek to create 3 scientific Cores that will each provide critical expertise and resources: the Structural Biology Core to offer critical insights into our Projects’ antiviral targets and mechanisms of action; the Pandemic Assistance Core to ensure adequate access to facilities with the requisite biosafety and containment to safely develop our Projects’ antivirals against SARS-CoV-2 and other potential RNA pandemic viruses; and the Translation Accelerator Core, in which is embedded the Industry Consultants Consortium, (ICC) to provide the requisite translational resources, industry rigor and expertise to advance each project in a milestone and Go/no-Go driven fashion. The range of planned activities spans the translational spectrum, from innovative target discovery and lead identification, to lead optimization and IND-enabling activities. Our antiviral modalities include small molecules, nucleic acids, and protein therapeutics. Our lead programs have demonstrated proof- of-concept in vivo antiviral efficacy, with the potential to combat coronaviruses, as well as other RNA viruses of pandemic potential. These efforts will include: a) targeting highly conserved RNA structures in viral RNA genomes with locked nucleic acid (LNA) antisense oligonucleotide (ASO) and small molecule therapeutics; b) improving formulations and delivery methods for nucleic acid therapeutics, and targeting virus-derived circular RNAs; c) selectively targeting viral envelopes antiviral peptides and peptoids; d) developing small molecule ligands of essential viral proteins that induce selective degradation of their protein targets; e) developing potent and selective inhibitors of essential proteases of SARS-CoV-2 and other RNA viruses; f) developing small molecule inhibitors of SARS-CoV-2 exonuclease to both promote lethal mutagenesis of the viral genome as well as enhance the antiviral efficacy of ribonucleoside analogs; g) developing small molecule inhibitors of SARS-CoV-2 NSP4’s role in membrane-associated RNA replication. We will establish an Administrative Core to effectively manage and optimally support the above, and provide critical regulatory expertise. Finally, we will leverage AViDD funding with institutional support, matching philanthropy and industry partnerships, and strategic relationships to maximize preclinical development and ensure successful clinical and commercial development of SyneRx’s most promising lead molecules. Successful accomplishment of our aims will yield exciting synergistic outpatient antiviral cocktails for SARS-CoV-2 and other RNA viruses of pandemic potential.

摘要：斯坦福 AViDD 中心“SyneRx”的总体平台和目标是开发 针对 SARS-CoV-2 和其他潜在大流行性 RNA 病毒的门诊抗病毒鸡尾酒。因此，目标是 我们的 7 个项目中的每一个项目都是为了临床开发一种新型直接作用抗病毒药物 (DAA)，其具有独特的作用 作用机制，使它们可以单独使用，也可以与其他药物联合使用——提供添加剂、 以及理想的协同抗病毒活性。为了最大限度地实现这一目标，我们力求创建 3 每个科学核心都将提供关键的专业知识和资源：结构生物学核心提供 对我们项目的抗病毒目标和作用机制的重要见解；流行病援助核心 确保有足够的机会使用具有必要的生物安全和遏制的设施，以安全地开发我们的 针对 SARS-CoV-2 和其他潜在 RNA 大流行病毒的项目抗病毒药物；和翻译 加速器核心，其中嵌入了行业顾问联盟 (ICC)，以提供必要的 翻译资源、行业严谨性和专业知识，以里程碑式的方式推进每个项目以及进行/不进行 引领时尚。计划活动的范围涵盖了从创新目标到转化范围 发现和先导化合物识别，以进行先导化合物优化和 IND 支持活动。我们的抗病毒方法 包括小分子、核酸和蛋白质疗法。我们的主导项目已证明- 概念上的体内抗病毒功效，具有对抗冠状病毒以及其他 RNA 病毒的潜力 大流行可能性。这些努力将包括：a) 针对病毒 RNA 中高度保守的 RNA 结构 具有锁核酸（LNA）反义寡核苷酸（ASO）和小分子疗法的基因组； b) 改进核酸治疗剂的配方和递送方法，并针对病毒衍生的循环 RNA； c)选择性靶向病毒包膜抗病毒肽和类肽； d) 开发小分子 必需病毒蛋白的配体，诱导其目标蛋白的选择性降解； e) 发展潜能 以及 SARS-CoV-2 和其他 RNA 病毒必需蛋白酶的选择性抑制剂； f) 发展小 SARS-CoV-2核酸外切酶的分子抑制剂可促进病毒基因组的致死突变 以及增强核糖核苷类似物的抗病毒功效； g) 开发小分子抑制剂 SARS-CoV-2 NSP4 在膜相关 RNA 复制中的作用。我们将设立行政 有效管理和最佳支持上述内容的核心，并提供关键的监管专业知识。最后， 我们将利用 AViDD 资金与机构支持、匹配慈善事业和行业合作伙伴关系，以及 战略关系，以最大限度地提高临床前开发并确保成功的临床和商业 SyneRx 最有前途的先导分子的开发。成功实现我们的目标将产生 针对 SARS-CoV-2 和其他具有大流行潜力的 RNA 病毒的令人兴奋的门诊协同抗病毒鸡尾酒。