Novel Artemisinin Derivatives for Cytomegalovirus Therapy

用于巨细胞病毒治疗的新型青蒿素衍生物

• 批准号: 8227951
• 负责人: Ravit Boger
• 金额: $ 41万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 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/8227951
• 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; public health relevance; research study; resistant strain; tool; transcription factor; viral DNA; viral resistance

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，成年后血清阳性率高达 90%。尽管正常宿主的感染通常是无症状的，但 CMV 会导致免疫功能低下人群（包括移植受者和感染 HIV 的患者）严重发病和死亡。 CMV 视网膜炎是艾滋病和严重免疫抑制患者的严重并发症。此外，先天性巨细胞病毒是美国智力低下和耳聋的主要原因。目前的巨细胞病毒疗法可以有效抑制病毒复制，但会导致严重的副作用以及耐药病毒的出现。新化合物的开发可以显着降低这种病原体的发病率和死亡率。本申请的总体目标是研究青蒿素的抗 CMV 活性。几种青蒿素衍生物广泛用于疟疾治疗。这些化合物可口服，并且具有良好的安全性。拟议的研究可以通过我们在约翰·霍普金斯大学开发的抗病毒检测方法和新合成的青蒿素衍生物来完成。我们最近报道，二聚青蒿素在抑制人成纤维细胞中 CMV 复制方面比单体形式更有效。我们还表明，CMV 复制的抑制发生在病毒复制的早期阶段。青蒿素的抗 CMV 机制可能与目前可用的化合物抑制 CMV 不同。我们建议鉴定最有效的抗 CMV 青蒿素衍生物，评估与已批准的抗 CMV 药物的组合是否具有相加作用，并阐明青蒿素抑制 CMV 复制的机制。该应用程序是可行且新颖的，因为我们已经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。从该应用中获得的信息将对 CMV 治疗产生重要影响。通过使用具有直接抗病毒靶点的化合物和针对对 CMV 复制重要的细胞蛋白的化合物的组合，它可能会带来 CMV 治疗的新概念。 公共卫生相关性：人类巨细胞病毒 (CMV) 感染是地方性流行病，与先天性感染的新生儿和免疫功能低下宿主的严重发病率和死亡率相关。 CMV 感染的治疗选择有限，开发针对 CMV 的新治疗策略非常重要。该提案的总体目标是确定青蒿素作为抗巨细胞病毒药物的活性和潜在机制。