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

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和其他潜在的大流行RNA病毒的门诊抗病毒鸡尾酒。因此，目标是 我们的7个项目中的每个项目都是向临床开发一种新的直接作用的抗病毒药物(DAA)，具有独特的 作用机制，以便它们可以单独使用，也可以与其他试剂结合使用--提供添加剂， 最理想的是协同抗病毒活性。为了最大限度地实现这一目标，我们寻求创造3个 将各自提供关键专业知识和资源的科学核心：将提供的结构生物学核心 对我们项目的抗病毒目标和行动机制的重要见解；大流行援助核心 确保充分进入具有必要生物安全和遏制措施的设施，以安全地发展我们的 针对SARS-CoV-2和其他潜在的RNA大流行病毒的项目的抗病毒药物； 加速器核心，其中嵌入了行业咨询公司联盟(ICC)，以提供必要的 翻译资源、行业严谨和专业知识，以推进每个项目的里程碑和通过/不通过 受时尚驱使。计划的活动范围跨越翻译范围，从创新目标 发现和领导识别，领导优化和支持IND的活动。我们的抗病毒设备 包括小分子、核酸和蛋白质疗法。我们的领先项目已经证明了- 概念体内抗病毒功效，具有对抗冠状病毒的潜力，以及其他核糖核酸病毒 大流行的可能性。这些努力将包括：a)针对病毒RNA中高度保守的RNA结构 带有锁定核酸(LNA)、反义寡核苷酸(ASO)和小分子疗法的基因组；b) 改进核酸治疗药物的配方和给药方法，并针对病毒衍生环状 RNA；c)选择性靶向病毒包膜、抗病毒多肽和类肽；d)开发小分子 诱导蛋白质靶标选择性降解的基本病毒蛋白的配体；e)形成有效的 和SARS-CoV-2和其他RNA病毒基本蛋白酶的选择性抑制剂；f)发展成小的 SARS-CoV-2核酸外切酶的分子抑制剂促进病毒基因组的致死性突变 以及增强核糖核苷类似物的抗病毒效果；g)开发小分子抑制剂 SARS冠状病毒NSP4‘S在膜相关核糖核酸复制中的作用。我们将建立一个行政管理机构 核心有效地管理和优化支持上述各项，并提供关键的监管专业知识。最后， 我们将通过机构支持、匹配慈善和行业合作伙伴关系来利用AViDD资金，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最有希望的铅分子的开发。成功地实现我们的目标将会产生 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.