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

摘要：斯坦福大学AViDD中心“SyneRx”的总体平台和目标是开发 针对SARS-CoV-2和其他潜在的大流行RNA病毒的门诊抗病毒鸡尾酒。因此， 我们的7个项目中的每一个都是为了临床开发一种新的直接作用的抗病毒药物（DAA）， 作用机制，因此它们可以单独使用，也可以与其他试剂-提供添加剂， 和理想的协同抗病毒活性。为了最大限度地实现这一目标，我们力求创造3 每个科学核心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;大流行病援助核心 确保充分利用具有必要的生物安全和遏制措施的设施，以安全地发展我们的 项目针对SARS-CoV-2和其他潜在的RNA大流行病毒的抗病毒药物; 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，以推进每个项目的里程碑和去/不去 赶时髦计划活动的范围涵盖了翻译范围，从创新目标到 发现和潜在客户识别，以领导优化和IND使能活动。我们的抗病毒疗法 包括小分子、核酸和蛋白质治疗剂。我们的主要项目已经证明- 概念体内抗病毒功效，具有对抗冠状病毒以及其他RNA病毒的潜力， 大流行的可能性。这些努力将包括：a）靶向病毒RNA中高度保守的RNA结构 具有锁核酸（LNA）反义寡核苷酸（阿索）和小分子治疗剂的基因组; B） 改进核酸治疗剂的制剂和递送方法，以及靶向病毒衍生的环状 RNA; c）选择性靶向病毒包膜的抗病毒肽和类肽; d）开发小分子 诱导其蛋白质靶标的选择性降解的必需病毒蛋白的配体; e）开发有效的 和SARS-CoV-2和其他RNA病毒的必需蛋白酶的选择性抑制剂; f）开发小的 SARS-CoV-2核酸外切酶的分子抑制剂，既能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）开发以下的小分子抑制剂： SARS-CoV-2 NSP 4在膜相关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工作，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， 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最有前途的铅分子的开发。成功地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病毒的令人兴奋的协同门诊抗病毒鸡尾酒。

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.