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：斯坦福大学AViDD中心“SyneRx”的总体平台和目标是开发