Novel Artemisinin Derivatives for Cytomegalovirus Therapy

用于巨细胞病毒治疗的新型青蒿素衍生物

基本信息

批准号：
8082274
负责人：
Ravit Boger
金额：
$ 41万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8082274
关键词：
Acquired Immunodeficiency Syndrome Adult Adverse effects Animal Model Antiviral Agents Artemisinins Biological Assay Cancer cell line Cells Clinical Complication Cytomegalovirus Cytomegalovirus Infections Cytomegalovirus Retinitis Cytomegalovirus Vaccines DNA Polymerase Inhibitor DNA-Directed DNA Polymerase Data Development Drug Combinations Endothelial Cells Environment Family Fibroblasts Future Ganciclovir Genes Genetic Transcription Goals HIV Herpesviridae Human Immunocompetent Immunocompromised Host Immunosuppression In Vitro Individual Infection Investigation Label Laboratories Lead Ligands Luciferases Malaria Mental Retardation Minocycline Modeling Morbidity - disease rate Newborn Infant Parents Pathway interactions Patients Pharmaceutical Preparations Protein Microchips Proteins Proteomics Rat Cytomegalovirus Recombinants Reporting Research Resistance Safety Series Seroprevalences Signal Pathway Staging Testing Therapeutic Effect Therapeutic Uses Time Transcript Translations Transplant Recipients United States Universities Viral Viral Proteins Virus Virus Diseases Virus Replication artemisinine artesunate burden of illness cellular targeting cohort congenital cytomegalovirus cost cytotoxic cytotoxicity deafness dimer effective therapy experience lytic replication monomer mortality novel novel therapeutics pathogen prophylactic protein expression research study resistant strain tool transcription factor viral DNA viral resistance

项目摘要

DESCRIPTION (provided by applicant): Cytomegalovirus (CMV) infection is common in humans, with seroprevalence rates reaching as high as 90% by adulthood. Although infection is usually asymptomatic in the normal host, CMV causes serious morbidity and mortality in immunocompromised cohorts, including transplant recipients and patients infected with HIV. CMV retinitis is a serious complication in patients with AIDS and profound immunosuppression. In addition, congenital CMV is the leading infectious cause of mental retardation and deafness in the United States. Current CMV therapies are effective in suppressing virus replication, but result in serious side effects, and the emergence of resistant viruses. Development of new compounds could significantly reduce morbidity and mortality from this pathogen. The overall goal of this application is to investigate the anti-CMV activities of artemisinins. Several artemisinin derivatives are widely used in malaria therapy. These compounds are orally available and have a good safety profile. The proposed investigation can be accomplished by our development of anti-viral assays and the availability of newly-synthesized artemisinin derivatives at Johns Hopkins University. We reported recently that dimeric artemisinins are dramatically more effective than the monomeric forms in inhibiting CMV replication in human fibroblasts. We have also shown that inhibition of CMV replication occurs at a very early stage of virus replication. The anti-CMV mechanism of artemisinins may be different than CMV inhibition by currently available compounds. We propose to identify the most potent anti-CMV artemisinin derivative, to evaluate whether combination with approved anti-CMV drugs is additive, and to elucidate mechanisms by which artemisinins inhibit CMV replication. This application is feasible and novel because we have acquired the experience and tools necessary for performing all experiments. For the first time we will use high throughput proteomics to identify the intracellular targets of artemisinins. The information derived from this application will have important impact on CMV therapy. It may lead to new concepts in CMV therapeutics by using a combination of compounds with direct anti-viral target and compounds which target a cellular protein that is important for CMV replication. PUBLIC HEALTH RELEVANCE: Infection with Human Cytomegalovirus (CMV) is endemic, and associated with severe morbidity and mortality in congenitally-infected newborns and immunocompromised hosts. Treatment options for CMV infection are limited, and it is important to develop new therapeutic strategies against CMV. The overall aim of this proposal is to determine the activities and potential mechanisms of artemisinins as anti-CMV drugs.

描述（由申请人提供）：巨细胞病毒（CMV）感染在人类中很常见，成年后血清阳性率达到高达90％。尽管在正常宿主中感染通常是无症状的，但CMV在免疫功能低下的队列中会导致严重的发病率和死亡率，包括移植受者和感染HIV的患者。 CMV视网膜炎是艾滋病患者和深层免疫抑制患者的严重并发症。此外，先天性CMV是美国智力低下和耳聋的主要传染病。当前的CMV疗法可有效抑制病毒复制，但会导致严重的副作用以及抗性病毒的出现。新化合物的发展可以显着降低这种病原体的发病率和死亡率。该应用的总体目标是研究青蒿素的抗CMV活性。几种青蒿素衍生物被广泛用于疟疾疗法。这些化合物可以口服，并具有良好的安全性。拟议的调查可以通过我们开发抗病毒测定法以及约翰·霍普金斯大学（Johns Hopkins University）的新合成的青蒿素衍生物的可用性来完成。我们最近报道说，二聚体青蒿素比单体形式在抑制人成纤维细胞中的CMV复制方面更有效。我们还表明，抑制CMV复制发生在病毒复制的早期阶段。阿默动蛋白的抗CMV机制可能与当前可用化合物的CMV抑制作用不同。我们建议确定最有效的抗CMV青蒿素衍生物，以评估与批准的抗CMV药物的组合是加性的，并阐明了青蒿素抑制CMV复制的机制。该应用程序是可行的和新颖的，因为我们获得了执行所有实验所需的经验和工具。我们将首次使用高通量蛋白质组学来鉴定青蒿素的细胞内靶标。从该应用程序得出的信息将对CMV疗法产生重要影响。它可能通过使用具有直接抗病毒靶标的化合物和靶向细胞蛋白的化合物组合来导致CMV疗法中的新概念，这对于CMV复制很重要。公共卫生相关性：与人类巨细胞病毒（CMV）的感染是地方性的，并且与先天感染的新生儿和免疫功能低下的宿主的严重发病率和死亡率有关。 CMV感染的治疗选择有限，重要的是制定针对CMV的新治疗策略。该提案的总体目的是确定阿梅米辛蛋白作为抗CMV药物的活性和潜在机制。