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Broad-spectrum antiviral GS-5734 to treat MERS-CoV and related emerging CoV

广谱抗病毒药物 GS-5734 用于治疗 MERS-CoV 和相关的新出现的 CoV

基本信息

批准号：
9977910
负责人：
Ralph S Baric
金额：
$ 116.67万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-09 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977910
关键词：
Address Animal Model Animals Antiviral Agents Antiviral Therapy Attenuated Biochemistry Birds Camels Cell Culture Techniques Cell model Cells Chiroptera Clinical Trials Coronavirus Coronavirus Infections Data Development Disease Disease Outbreaks Drug Kinetics Endothelium Engineering Epithelial Cells Exons Family Filovirus Fluorescent in Situ Hybridization Fostering Future Generations Genetic Genetic Variation Genome Goals Hepatitis Human Immune In Vitro Infection Innate Immune Response Licensure Lung Mammals Measurement Mediating Medical Metabolic Metabolism Metagenomics Middle East Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Modeling Mus Mutate Mutation Nucleosides Parents Pathogenesis Pathogenicity Pathway interactions Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Predisposition Primates Prodrugs Proteins Public Health RNA RNA Viruses RNA chemical synthesis RNA replication RNA-Directed RNA Polymerase Recovery Resistance Resistance profile Resolution SARS coronavirus Science Serum Severe Acute Respiratory Syndrome T-Lymphocyte Testing Therapeutic Toxic effect Transgenic Mice Treatment Efficacy Viral Genome Viral Pathogenesis Virus Virus Replication Wild Animals Zoonoses aged airway epithelium alveolar type II cell animal ecology anti-viral efficacy antiviral immunity biological systems clinical application coronavirus receptor cross-species transmission deep sequencing design drug metabolism efficacy study esterase fitness human coronavirus human disease human model improved in vivo in vivo evaluation in vivo imaging metabolic abnormality assessment mouse model nonhuman primate novel coronavirus pandemic disease pathogenic virus pharmacokinetics and pharmacodynamics pre-clinical preclinical development programs recombinant virus remdesivir replicase resistance mutation single molecule transcriptome sequencing tripolyphosphate uptake viral RNA viral fitness virology

项目摘要

Project Summary Zoonotic viruses, like filoviruses and coronaviruses (CoV), represent a continuous and growing threat to global public health because they unpredictably emerge causing devastating outbreaks of pandemic disease. In the 21st century, severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) emerged from zoonotic pools of viruses, causing severe disease in humans. MERS-CoV is endemic in camels in the Middle East with continuous new infections in humans. Although SARS-CoV is not currently a threat, several “prepandemic” SARS-like CoVs have been isolated from bats that replicate efficiently in human cells and are resistant to existing therapies. With the unpredictable overlap of human and wild animal ecologies, the potential for novel CoV emergence into humans is highly probable. Currently, there are no approved antiviral therapies for any human CoV infection. Broad-spectrum CoV therapies that control known human and zoonotic CoV infections would address an immediate unmet medical need and could counter future pandemic episodes. In partnership with Gilead Sciences, we have demonstrated that the nucleoside prodrug, GS-5734, is highly efficacious in inhibiting multiple human and zoonotic CoV in vitro and SARS-CoV in vivo. The primary goal of our program is to accelerate the preclinical development of GS-5734 and promote IND licensure for the MERS-CoV indication. To thoroughly evaluate the breadth of antiviral activity and predict efficacy against future emerging CoV, we will also assess efficacy against a panel of CoV representative of family-wide genetic diversity, including prepandemic zoonotic strains poised for emergence. Focusing on the highly pathogenic MERS-CoV, our unique partnership integrates: i) metagenomics and recombinant virus synthetic genome recovery, ii) primary human lung cell models, iii) cutting edge virology and biochemistry, iv) robust murine and primate models of human disease and v) state of the art metabolic and pharmacokinetic analysis. In Aim 1, we refine the pharmacokinetics, pharmacodynamics and breadth of GS-5734 through efficacy and metabolism studies in various primary human cells with a diverse array of human and zoonotic CoV and through the evaluation of in vivo efficacy in murine and non-human primate models of MERS- and SARS-CoV. In Aim 2, we select for resistance against SARS-CoV and MERS- CoV, and determine the effect of resistance on virus replication, fitness and susceptibility to treatment. In Aim 3, we determine if the mechanism of action of GS-5734 is a result of direct effects on viral RNA replication and/or alteration of antiviral immunity via deep sequencing and single molecule RNA fluorescence in situ hybridization of vehicle or drug treated infected cells and mice. We articulate a development strategy for broad- spectrum therapeutics that could be extended to a multitude of emerging viral pathogens threatening global public health.

项目概要人畜共患病病毒，如丝状病毒和冠状病毒 (CoV)，对全球构成持续且日益增长的威胁公共卫生，因为它们不可预测地出现，导致毁灭性的流行病爆发。在 21世纪，严重急性呼吸综合征冠状病毒（SARS-CoV）与中东呼吸道疾病综合症冠状病毒（MERS-CoV）从人畜共患病病毒库中出现，在人类中引起严重疾病人类。 MERS-CoV 在中东的骆驼中流行，人类中不断有新的感染。尽管 SARS-CoV 目前并不构成威胁，但已从其中分离出几种“大流行前”的 SARS 样 CoV。蝙蝠在人类细胞中有效复制并且对现有疗法具有抵抗力。与不可预知的人类和野生动物生态系统重叠，新型冠状病毒出现在人类身上的可能性很高可能。目前，还没有批准的针对任何人类冠状病毒感染的抗病毒疗法。广谱控制已知人类和人畜共患冠状病毒感染的冠状病毒疗法将解决当前未得到满足的问题医疗需求，并可以应对未来的大流行病。我们与吉利德科学公司合作，证明核苷前药 GS-5734 在抑制多种人类和体外人畜共患冠状病毒和体内SARS-CoV。我们计划的主要目标是加速临床前研究开发 GS-5734 并促进 MERS-CoV 适应症的 IND 许可。为了彻底评估抗病毒活性的广度并预测针对未来新出现的冠状病毒的功效，我们还将评估功效针对代表全科遗传多样性的一组冠状病毒，包括大流行前的人畜共患菌株准备出现。专注于高致病性中东呼吸综合征冠状病毒，我们独特的合作伙伴关系包括：i) 宏基因组学和重组病毒合成基因组恢复，ii) 原代人肺细胞模型，iii) 尖端病毒学和生物化学，iv) 人类疾病的稳健小鼠和灵长类动物模型，以及 v) 状态先进的代谢和药代动力学分析。在目标 1 中，我们完善了药代动力学、药效学通过对各种原代人类细胞进行功效和代谢研究，了解 GS-5734 的广度和广度一系列人类和人畜共患冠状病毒，并通过评估小鼠和非人类的体内功效 MERS 和 SARS-CoV 的灵长类动物模型。在目标 2 中，我们选择对 SARS-CoV 和 MERS 具有抵抗力冠状病毒，并确定耐药性对病毒复制、适应性和治疗敏感性的影响。瞄准 3、我们确定GS-5734的作用机制是否是直接影响病毒RNA复制的结果和/或通过深度测序和单分子 RNA 原位荧光改变抗病毒免疫力载体或药物处理的受感染细胞和小鼠的杂交。我们制定了广泛的发展战略谱疗法可以扩展到威胁全球的多种新兴病毒病原体公共卫生。