Project 1 - Coronavirus

项目 1 - 冠状病毒

基本信息

批准号：
10115596
负责人：
Mark R Denison
金额：
$ 103.11万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10115596
关键词：
Acute Address Adult Respiratory Distress Syndrome Animals Antiviral Agents Antiviral resistance Cell Culture Techniques Cells Clinical Trials Combined Modality Therapy Coronavirus Cultured Cells Data Development Disease Drug Kinetics Drug resistance Epidemic Evaluation Exons Exoribonucleases FDA approved Future Genome Goals Human Immunomodulators In Vitro Infection Innate Immune Response Institutes Lead Lung Lung diseases Medical Metabolism Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Mus Mutagens Natural Immunity Pathogenesis Pathogenicity Pathology Pharmaceutical Preparations Prevention RNA RNA Viruses RNA-Directed RNA Polymerase Research Resistance Resistance development SARS coronavirus Science Severe Acute Respiratory Syndrome Testing Therapeutic Therapeutic Effect Treatment Efficacy Treatment Protocols Virulence Virus Virus Replication Work Zoonoses aged airway epithelium anti-viral efficacy antiviral nucleoside analog coronavirus antiviral coronavirus disease coronavirus treatment cytotoxicity deep sequencing drug development drug discovery drug efficacy effective therapy efficacy evaluation fitness immunoregulation immunosuppressed in vivo inhibitor/antagonist mortality mouse model novel novel coronavirus nucleoside analog pandemic disease pathogenic virus preclinical development prevent programs prophylactic remdesivir research clinical testing resistance mutation respiratory infection virus response screening small molecule therapeutically effective tool transmission process viral RNA viral fitness zoonotic coronavirus

项目摘要

PROJECT SUMMARY Zoonotic coronaviruses (CoVs) such as SARS-CoV and MERS-CoV are pandemic threats. MERS-CoV continues to cause new zoonotic and human transmission and illness with ~35% mortality. Currently, there are no FDA-approved therapies to treat any CoV. New zoonotic CoVs likely will emerge from heterogeneous virus pools in animal reservoirs, thus requiring antiviral strategies aimed at completely conserved and vulnerable targets. CoVs rapidly select for resistance to multiple classes of inhibitors, demonstrating the need for approaches to prevent resistance emergence. Both SARS and MERS infections manifest as severe immunopathologic damage, potentially limiting the therapeutic window for direct-acting antivirals (DAAs). Immunomodulation in the absence of antivirals has been shown to not be beneficial and to even exacerbate SARS and MERS disease. Thus, combinations of DAAs and targeted immunomodulators may be necessary for effective treatment of established infection. The overall goal of our program is to develop CoV antiviral strategies that broadly inhibit known and future potential pandemic zoonotic CoVs, prevent emergence of resistance, and extend the therapeutic window by targeting host immunopathologic responses. The proposed research will advance preclinical development of the CoV-inhibitory nucleoside analogue EIDD- 1931/2801 and other nucleoside analogues in the pipeline and test two small-molecule hits identified as highly active against SARS-CoV for treatment and prevention of epidemic and pre-emergent CoVs. In Specific Aim 1, the spectrum of antiviral activity and therapeutic efficacy of compounds will be defined. The antiviral efficacy, metabolism, and cytotoxicity of each compound will be determined in cultures of primary human lung cells targeted by SARS-CoV and MERS-CoV. The prophylactic and therapeutic efficacy of lead compounds will be evaluated in young, aged, and immunosuppressed murine models of SARS and MERS pathogenesis. In Specific Aim 2, the mechanism of action of lead compounds and kinetics of drug resistance will be determined. The antiviral effect of compounds on virus replication, fidelity, and induction of innate immunity will be assessed. Resistance mutations in genomes of MERS-CoV and SARS-CoV passaged in the presence of increasing concentrations of drug will be determined by deep sequencing. The impact of resistance on SARS-CoV and MERS- CoV virulence, sensitivity to other drugs, and therapeutic efficacy of lead compounds will be determined. Specific Aim 3 will focus on the development of combination regimens for the treatment of emerging CoVs. The combined therapeutic efficacy of DAAs against infections with both wild-type and drug-resistant SARS-CoV and MERS-CoV will be defined using cultured cells and mice. The therapeutic effect of treatment combining a DAA with an immunomodulator will be assessed in mouse models of SARS and MERS. These studies will generate mechanistic and efficacy data necessary for IND filing and origination of human clinical trials.

项目概要 SARS-CoV 和 MERS-CoV 等人畜共患冠状病毒 (CoV) 是大流行威胁。中东呼吸综合征冠状病毒继续导致新的人畜共患和人类传播和疾病，死亡率约为 35%。目前，有没有 FDA 批准的治疗任何 CoV 的疗法。新的人畜共患冠状病毒可能会从异质病毒中出现动物储存库中的水池，因此需要针对完全保守和脆弱的抗病毒策略目标。冠状病毒迅速选择对多种抑制剂产生耐药性，这表明需要防止耐药性出现的方法。 SARS 和 MERS 感染均表现为严重免疫病理损伤，可能限制直接作用抗病毒药物（DAA）的治疗窗口。在没有抗病毒药物的情况下进行免疫调节已被证明是没有好处的，甚至会加剧 SARS 和 MERS 疾病。因此，DAA 和靶向免疫调节剂的组合可能是必要的有效治疗已确定的感染。我们计划的总体目标是开发冠状病毒抗病毒药物广泛抑制已知和未来潜在大流行人畜共患冠状病毒、防止出现的策略耐药性，并通过针对宿主免疫病理反应来延长治疗窗。这拟议的研究将推进 CoV 抑制核苷类似物 EIDD 的临床前开发 1931/2801 和管道中的其他核苷类似物，并测试了两个被确定为高度的小分子命中有效对抗 SARS-CoV，用于治疗和预防流行病和出现前的 CoV。在具体目标 1 中，将定义化合物的抗病毒活性谱和治疗功效。抗病毒功效，每种化合物的代谢和细胞毒性将在原代人肺细胞培养物中测定 SARS-CoV 和 MERS-CoV 的目标。先导化合物的预防和治疗功效将是在 SARS 和 MERS 发病机制的年轻、老年和免疫抑制小鼠模型中进行了评估。在具体目标2，将确定先导化合物的作用机制和耐药动力学。将评估化合物对病毒复制、保真度和先天免疫诱导的抗病毒作用。 MERS-CoV 和 SARS-CoV 基因组中的耐药突变在存在增加的情况下传代药物浓度将通过深度测序确定。耐药性对 SARS-CoV 和 MERS 的影响将确定冠状病毒的毒力、对其他药物的敏感性以及先导化合物的治疗效果。具体目标 3 将侧重于开发治疗新出现的冠状病毒的联合方案。这 DAA 对野生型和耐药 SARS-CoV 感染的综合治疗功效 MERS-CoV 将使用培养细胞和小鼠进行定义。联合DAA治疗的疗效将在 SARS 和 MERS 小鼠模型中评估免疫调节剂的作用。这些研究将产生 IND 备案和人体临床试验发起所需的机制和功效数据。