Novel Artemisinin Derivatives for Cytomegalovirus Therapy

描述(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%。虽然在正常宿主中通常没有感染症状，但CMV在免疫功能低下的人群中会导致严重的发病率和死亡率，包括移植受者和感染艾滋病毒的患者。巨细胞病毒视网膜炎是艾滋病患者的严重并发症和严重的免疫抑制。此外，在美国，先天性巨细胞病毒是导致智力低下和耳聋的主要传染病。目前的CMV疗法在抑制病毒复制方面是有效的，但会导致严重的副作用，并出现耐药病毒。开发新的化合物可以显著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。几种青蒿素衍生物被广泛用于疟疾治疗。这些化合物是口服的，具有良好的安全性。这项拟议的研究可以通过我们开发的抗病毒试验和约翰霍普金斯大学新合成的青蒿素衍生物的可用性来完成。我们最近报道，在抑制人成纤维细胞中的CMV复制方面，二聚体青蒿素比单体形式显著更有效。我们还表明，CMV复制的抑制发生在病毒复制的非常早期阶段。青蒿素的抗CMV作用机制可能不同于现有化合物对CMV的抑制作用。我们建议确定最有效的抗CMV青蒿素衍生物，评估与已批准的抗CMV药物是否具有相加作用，并阐明青蒿素抑制CMV复制的机制。这一应用是可行的和新颖的，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确定青蒿素的细胞内靶点。从这一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复制至关重要的细胞蛋白的化合物的组合，它可能会在CMV治疗中产生新的概念。

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.