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：Stanford Avidd中心的总体平台和目标是“ Synerx” 针对SARS-COV-2和其他潜在的大流行RNA病毒的门诊抗病毒鸡尾酒。那是 我们的7个项目中的每个项目都是向诊所开发的一种新型直接作用抗病毒（DAA） 作用机理，以便它们可以单独使用并与其他代理联合使用，以提供添加剂， 理想情况下是协同抗病毒活性。为了最大化这个目标的实现，我们试图创建3 每个将提供关键专业知识和资源的科学核心：提供的结构生物学核心 对我们项目的抗病毒目标和作用机制的批判性见解；大流行援助核心 为了确保具有必要的生物安全和遏制以安全地开发我们的设施 针对SARS-COV-2和其他潜在RNA大流行病毒的项目抗病毒药；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，行业严格和专业知识，以一个里程碑推进每个项目 驱动的时尚。计划中的活动范围跨越了翻译的频谱，从创新目标 发现和铅识别，以领导优化和辅助活动。我们的抗病毒方式 包括小分子，核酸和蛋白质治疗。我们的主要计划已证明了证明 - 体内抗病毒效率的概念，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）靶向病毒RNA中高度组成的RNA结构 具有锁定核酸（LNA）反义寡核苷酸（ASO）和小分子治疗的基因组； b） 改善核酸疗法的公式和递送方法，并靶向病毒衍生的循环 rnas; c）选择性靶向病毒包络抗病毒肽和肽； d）发展小分子 必需病毒蛋白的配体，诱导其蛋白质靶标的选择性降解； e）发展有效 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外切核酸酶的分子抑制剂既促进病毒基因组的致死诱变， 以及提高色带类似物类似物的抗病毒效率； g）开发小分子抑制剂 SARS-COV-2 NSP4在与膜相关的RNA复制中的作用。我们将建立一个行政 有效管理和最佳支持上述并提供关键的监管专业知识的核心。最后， 我们将利用Avidd资助，并提供机构支持，慈善和行业合作伙伴关系，以及 战略关系以最大化临床前发展并确保成功的临床和商业 开发Synerx最有希望的铅分子。成功实现我们的目标将产生 令人兴奋的SARS-COV-2和其他大流行潜力RNA病毒的令人兴奋的协同门诊抗病毒鸡尾酒。