Alternative antiviral drug targets for human cytomegalovirus infection

描述(由申请人提供)： 人巨细胞病毒(CMV)是一种主要的机会性病毒病原体，可引起视网膜炎、肺炎、结肠炎和脑炎等侵袭性疾病中的免疫低下。艾滋病和移植的成功治疗包括有效抑制巨细胞病毒感染，通常需要长期的抗病毒治疗。目前的治疗方法以更昔洛韦、磷甲酸钠和西多福韦为基础，只有一个病毒靶点(DNA聚合酶)，而且存在剂量限制性毒性、抗病毒耐药性和交叉耐药。尽管有强烈的临床需求和有希望的替代抗病毒药物靶点，但多年来没有新药获得FDA的批准。CMV UL97激酶抑制剂maribavir是一种重要的新治疗选择，因为它具有口服生物利用度，是一个独特的病毒靶点，而且与目前获得许可的药物没有交叉耐药性。在过去的资助期间，这项研究计划确定了病毒UL97和UL27突变，使maribavir耐药性得以及时得到及时的基因诊断，这是迄今为止已知的唯一对该药物产生耐药性的maribavir治疗对象。此外，观察到细胞培养条件对体外maribavir敏感性的影响，以及细胞抗代谢药物的协同作用，提示maribavir与细胞激酶抑制剂联合使用可能是有益的。(4)评估具有明确CMV药物靶点的有前景的实验化合物的治疗潜力，包括效力、协同作用以及耐药和交叉耐药倾向。人们的期望是，理想的抑制CMV疗法可能涉及具有不同作用机制的药物的组合，这可能会减少耐药性的发生率，就像在治疗其他慢性病毒感染时一样。 公共卫生相关性： 巨细胞病毒感染管理的改进使所有患有艾滋病或接受器官移植的退伍军人受益。退伍军人管理局是肝脏移植的主要供应商，特别是在我们的波特兰退伍军人医疗中心。目前，抗CMV药物通常在移植后几个月内给予，以试图抑制CMV疾病，但长期使用受到毒性和耐药性的限制。这导致了延迟巨细胞病毒病的病例，因为治疗被取消了。这项研究的目标是改善对CMV耐药性的早期认识，以及使用具有独特和协同抗病毒作用的口服活性药物，应该会提高这种慢性病毒感染的管理成本和有效性。维持治疗可能有助于减轻移植后CMV感染的间接炎症效应，如移植物血管病变或严重的复发性肝炎。

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.