Alternative antiviral drug targets for human cytomegalovirus infection

人类巨细胞病毒感染的替代抗病毒药物靶点

• 批准号: 8245576
• 负责人: Sunwen Chou
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8245576
• 关键词: Acquired Immunodeficiency Syndrome; Antimetabolites; Antiviral Agents; Antiviral Therapy; Biological Assay; Biological Availability; Cell Culture Techniques; Chronic; Cidofovir; Clinical; Colitis; Cytomegalovirus; Cytomegalovirus Infections; DNA-Directed DNA Polymerase; Diagnosis; Disease; Dose; Dose-Limiting; Drug Combinations; Drug Delivery Systems; Drug resistance; Drug usage; Early Diagnosis; Encephalitis; Evolution; FDA approved; Foscarnet; Funding; Ganciclovir; Genes; Genetic; Growth; Hepatitis; Immunocompromised Host; In Vitro; Incidence; Infection; Inflammatory; Kinetics; Label; Laboratories; Licensing; Maintenance Therapy; Medical center; Mutation; Oral; Organ Transplantation; Pathway interactions; Pharmaceutical Preparations; Phase; Phase I/II Trial; Pneumonia; Predisposition; Property; Prophylactic treatment; Proteins; Provider; Recurrence; Refractory; Relative (related person); Reporter; Reporting; Research; Resistance; Resistance development; Retinitis; Serial Passage; Staging; Targeted Research; Technology; Therapeutic; Toxic effect; Transplantation; Vascular Diseases; Veterans; Viral; Viral Drug Resistance; Virus; Virus Diseases; base; cell type; cost effectiveness; expectation; fitness; improved; in vivo; kinase inhibitor; liver transplantation; maribavir; mutant; open label; pathogen; programs; public health relevance; resistance mutation

DESCRIPTION (provided by applicant): Human cytomegalovirus (CMV) is a leading opportunistic viral pathogen, causing invasive disease such as retinitis, pneumonia, colitis and encephalitis in the immunocompromised. Successful management of AIDS and transplantation includes effective suppression of CMV infection, often involving prolonged antiviral therapy. Current therapy, based on ganciclovir, foscarnet and cidofovir, has a single viral target (DNA polymerase), and is complicated by dose-limiting toxicity, antiviral drug resistance and cross-resistance. Despite a strong clinical need and promising alternative antiviral drug targets, no new drugs have been FDA-approved in many years. The CMV UL97 kinase inhibitor maribavir is an important new treatment option because of oral bioavailability, a distinct viral target, and lack of cross-resistance with currently licensed drugs. After successful Phase I and II trials, ViroPharma conducted low-dose Phase III post-transplant prophylaxis trials which were unsuccessful but widely regarded as insufficiently dosed, because open label use of the drug at a higher dose appeared to salvage the treatment of several cases of refractory or drug-resistant CMV disease. During the past funding period, this research program identified viral UL97 and UL27 mutations that confer maribavir resistance, allowing for the timely genotypic diagnosis of the only maribavir-treated subject so far known to have developed resistance to this drug. In addition, the observed effects of cell culture conditions on in vitro maribavir susceptibility, and the synergistic effect of cellular antimetabolites, suggested that use of maribavir in combination with cellular kinase inhibitors may be beneficial. In the upcoming project period, research objectives pertaining to maribavir and other CMV antivirals are (1) use contemporary deep sequencing technology to track the evolution of drug resistance mutations, potentially enabling the earlier detection of impending resistance; (2) further develop phenotypic assays for CMV drug resistance by modifying control laboratory strains in genes UL128-131 to give them growth properties more similar to fresh clinical isolates, (3) evaluate the reported anti-CMV activity of cellular antimetabolites in clinical use for other indications, alone and in combination with existing antivirals; (4) assess the therapeutic potential of promising experimental compounds with defined CMV drug targets, with respect to potency, synergy, and propensity to resistance and cross-resistance. The expectation is that an ideally suppressive CMV therapy may involve a combination of drugs with different mechanisms of action, which could reduce the incidence of drug resistance, as in the treatment of other chronic viral infections. PUBLIC HEALTH RELEVANCE: Improved management of CMV infection benefits all veterans with AIDS or who receive organ transplants. VA is a major provider of liver transplantation, especially at our Portland VA Medical Center. Currently, anti-CMV drugs are usually given for several months post-transplant in an attempt to suppress CMV disease, but prolonged use is limited by toxicity and resistance. This leads to cases of delayed CMV disease as therapy is withdrawn. Improved early recognition of CMV drug resistance and use of orally active agents with distinct and synergistic antiviral actions, as targeted by this research, should improve the cost and effectiveness of managing of this chronic viral infection. Maintenance therapy may help to mitigate the indirect inflammatory effects of post-transplant CMV infection such as graft vasculopathy or severe recurrent hepatitis.

描述（由申请人提供）： 人类巨细胞病毒（CMV）是一种领先的机会性病毒病原体，在免疫功能低下引起了侵袭性疾病，例如视网膜炎，肺炎，结肠炎和脑炎。成功管理艾滋病和移植包括有效抑制CMV感染，通常涉及长时间的抗病毒疗法。基于Ganciclovir，Foscarnet和Cidofovir的当前疗法具有单个病毒靶靶（DNA聚合酶），并且由于剂量限制毒性，抗病毒耐药性和交叉抗性而变得复杂。尽管临床需求很强和有希望的替代抗病毒药物靶标，但多年来，未经FDA批准了新药。 CMV UL97激酶抑制剂Maribavir是一种重要的新治疗选择，因为口服生物利用度，独特的病毒靶标，并且缺乏与当前有执照的药物的交叉抗性。在成功进行了I期和II期试验之后，ViroPharma进行了低剂量的III期移植后预防试验，这些试验未成功，但被广泛认为是剂量不足，因为在较高剂量上对药物的开放标记使用似乎是为了萨尔维奇而征服了几种冷冻或药物抗药性的CMV疾病的治疗方法。在过去的资金期间，该研究计划确定了赋予马里巴韦抗性的病毒UL97和UL27突变，从而允许及时对迄今为止唯一的Maribavir治疗的受试者进行基因型诊断，迄今已知已经产生了对这种药物的抵抗力。此外，观察到的细胞培养条件对体外马里巴维尔易感性的影响以及细胞抗代谢物的协同作用，表明使用马里巴韦与细胞激酶抑制剂结合使用可能是有益的。在即将到来的项目时期，与Maribavir和其他CMV抗病毒有关的研究目标是（1）使用当代的深层测序技术来跟踪耐药性突变的演变，从而有可能早期发现即将抗性的耐药性； （2）进一步开发了通过修饰基因中的控制实验室菌株UL128-131中的控制实验室菌株的表型测定，使它们的生长特性与新鲜临床分离株更相似，（3）评估据报道，据报道，据报道，单独和与现有抗病毒物结合使用临床使用中细胞抗代谢物的抗CMV活性； （4）评估具有定义的CMV药物靶标的有希望的实验化合物的治疗潜力，这些化合物在耐药性，耐药性和抗性倾向方面。预期的是，理想的抑制性CMV疗法可能涉及具有不同作用机理的药物的组合，这可能会降低耐药性的发生，例如治疗其他慢性病毒感染。 公共卫生相关性： 改善CMV感染的管理使所有具有AIDS或接受器官移植的退伍军人受益。弗吉尼亚州是肝脏移植的主要提供商，尤其是在我们的波特兰弗吉尼亚州医疗中心。目前，移植后几个月以抗CMV疾病的疾病，通常给予抗CMV药物，但长时间使用受到毒性和抗性的限制。这导致由于撤回治疗而导致CMV疾病延迟的病例。这项研究的针对性，改善了对具有独特和协同抗病毒作用的口服抗药性药物的早期识别，并使用具有独特和协同的抗病毒作用的使用，应提高管理这种慢性病毒感染的成本和有效性。维持治疗可能有助于减轻移植后CMV感染（如移植血管病或严重复发性肝炎）的间接炎症作用。