Novel Artemisinin Derivatives for Cytomegalovirus Therapy

描述（由申请人提供）：巨细胞病毒（CMV）感染在人类中很常见，成年时血清阳性率高达90%。虽然感染通常是无症状的正常主机，CMV导致严重的发病率和死亡率在免疫功能低下的队列，包括移植受体和感染艾滋病毒的患者。巨细胞病毒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迟钝和耳聋的主要传染性原因。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和耐药病毒的出现。开发新的化合物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，具有良好的安全性。这项研究可以通过我们开发的抗病毒检测方法和约翰霍普金斯大学新合成的青蒿素衍生物来完成。我们最近报道了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机制可能不同于目前可用的化合物对CMV的抑制。我们建议确定最有效的抗CMV青蒿素衍生物，以评估是否与批准的抗CMV药物的组合是添加剂，并阐明青蒿素抑制CMV复制的机制。这种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鉴定青蒿素的细胞内靶点。从该应用程序中获得的信息将对CMV治疗产生重要影响。通过使用具有直接抗病毒靶标的化合物和靶向对CMV复制重要的细胞蛋白质的化合物的组合，可能导致CMV治疗的新概念。

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.