Alternative antiviral drug targets for human cytomegalovirus infection

描述（由申请人提供）： 人巨细胞病毒（Human cytomegalovirus，CMV）是一种重要的机会致病性病毒，在免疫功能低下的人群中可引起视网膜炎、肺炎、结肠炎和脑炎等侵袭性疾病。艾滋病和移植的成功管理包括有效抑制CMV感染，通常涉及长期的抗病毒治疗。目前的治疗，更昔洛韦，膦甲酸和西多福韦的基础上，有一个单一的病毒靶点（DNA聚合酶），并通过剂量限制性毒性，抗病毒药物耐药性和交叉耐药性复杂。尽管有强大的临床需求和有前途的替代抗病毒药物靶点，但多年来没有新药获得FDA批准。CMV UL 97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、独特的病毒靶点，并且与目前许可的药物缺乏交叉耐药性。在成功的I期和II期试验后，ViroPharma进行了低剂量的III期移植后预防性试验，这些试验不成功，但被广泛认为剂量不足，因为以较高剂量开放标签使用药物似乎挽救了几例难治性或耐药CMV疾病的治疗。在过去的资助期间，该研究项目确定了赋予Maribavir耐药性的病毒UL 97和UL 27突变，从而能够及时对迄今为止已知对该药物产生耐药性的唯一Maribavir治疗受试者进行基因型诊断。此外，观察到的细胞培养条件对体外Maribavir敏感性的影响以及细胞抗代谢物的协同作用表明，Maribavir与细胞激酶抑制剂联合使用可能有益。在即将到来的项目期间，与Maribavir和其他CMV抗病毒药物相关的研究目标是（1）使用当代深度测序技术跟踪耐药突变的演变，可能有助于早期检测即将发生的耐药性;（2）通过在基因UL 128 - 129中修饰对照实验室菌株，进一步开发CMV抗药性的表型测定法。（3）评价细胞抗代谢物在临床上用于其他适应症时单独或与现有抗病毒药物联合使用的抗CMV活性;（4）评估具有确定的CMV药物靶标的有前景的实验化合物的治疗潜力，涉及效力、协同作用以及耐药性和交叉耐药性的倾向。期望的是，理想的抑制性CMV治疗可能涉及具有不同作用机制的药物组合，这可以降低耐药性的发生率，如在治疗其他慢性病毒感染中一样。

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.