Project 1 - Coronavirus

项目 1 - 冠状病毒

基本信息

批准号：
10580022
负责人：
Mark R Denison
金额：
$ 102.98万
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 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580022
关键词：
Acute Acute Respiratory Distress Syndrome Address 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 Lead Lung Lung diseases Medical Metabolism Middle East Respiratory Syndrome Middle East Respiratory Syndrome Coronavirus Mus Mutagens Natural Immunity Pathogenesis Pathogenicity Pathology Pharmaceutical Preparations 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 Viral Viral Physiology 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 drug resistance development effective therapy efficacy evaluation fitness future pandemic immune modulating agents immunoregulation immunosuppressed in vivo inhibitor mortality mouse model novel novel coronavirus nucleoside analog pandemic coronavirus pandemic potential pathogenic virus preclinical development prevent prevent epidemics 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.

项目摘要人畜共努性冠状病毒（COV），例如SARS-COV和MERS-COV是大流行威胁。 mers-cov 继续引起新的人畜共患病和人类传播以及约35％的死亡率。目前，有没有FDA批准的疗法来治疗任何COV。新的动物COV可能会从异质病毒中出现动物储层中的池，因此需要旨在完全保守和脆弱的抗病毒药策略目标。 COV迅速选择对多种类别抑制剂的抵抗力，证明了对防止抵抗出现的方法。 SARS和MERS感染都表现为严重免疫病理损害，可能限制直接作用抗病毒药的治疗窗口（DAAS）。在没有抗病毒药的情况下，免疫调节已被证明不有益，甚至不加恶心 SARS和MERS病。因此，对于DAA和靶向免疫调节剂的组合可能是必需的有效治疗已建立的感染。我们计划的总体目标是开发COV抗病毒广泛抑制已知和未来潜在大流行的人畜共患病的策略，防止出现抗药性，并通过靶向宿主免疫病理反应来扩展治疗窗口。这拟议的研究将推动COV抑制性核苷类似物EIDD-的临床前发展 1931/2801和管道中的其他核苷类似物，并测试了两个小分子命中活跃于SARS-COV治疗和预防流行病和出现前COV的活动。在特定的目标1中，将定义化合物的抗病毒活性和治疗功效的光谱。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的培养物中确定由SARS-COV和MERS-COV瞄准。铅化合物的预防性和治疗功效将是在SARS和MERS发病机理的年轻，老年和免疫抑制的鼠模型中进行评估。在具体目标2，将确定铅化合物的作用机理和耐药性的动力学。化合物对病毒复制，忠诚度和先天免疫诱导的抗病毒作用将得到评估。在增加的情况下，MERS-COV和SARS-COV基因组中的抗性突变在增加药物的浓度将通过深层测序确定。抵抗对SARS-COV和MERS的影响 - 将确定COV毒力，对其他药物的敏感性以及铅化合物的治疗功效。特定的目标3将集中于用于治疗新兴COV的组合方案的发展。这 DAA对野生型和耐药的SARS-COV和耐药性感染的治疗功效以及 MERS-COV将使用培养的细胞和小鼠定义。结合DAA的治疗的治疗作用使用免疫调节剂将在SARS和MER的小鼠模型中进行评估。这些研究将产生人类临床试验的IND提交和起源所需的机械和功效数据。