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: 8696793
• 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/8696793
• 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 Targeting; 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; deep sequencing; expectation; fitness; improved; in vivo; kinase inhibitor; liver transplantation; maribavir; mutant; open label; pathogen; programs; 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.

描述（由申请人提供）： 人类巨细胞病毒（CMV）是一种主要的机会性病毒病原体，可在免疫功能低下者中引起侵袭性疾病，如视网膜炎、肺炎、结肠炎和脑炎。艾滋病和移植的成功管理包括有效抑制 CMV 感染，通常涉及长期抗病毒治疗。目前的治疗基于更昔洛韦、膦甲酸和西多福韦，具有单一病毒靶点（DNA聚合酶），并且由于剂量限制性毒性、抗病毒药物耐药性和交叉耐药性而变得复杂。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 批准。 CMV UL97 激酶抑制剂马瑞巴韦是一种重要的新治疗选择，因为它具有口服生物利用度、独特的病毒靶标，并且与目前许可的药物不存在交叉耐药性。在成功进行 I 期和 II 期试验后，ViroPharma 进行了低剂量 III 期移植后预防试验，这些试验未成功，但广泛认为剂量不足，因为开放标签使用较高剂量的药物似乎可以挽救几例难治性或耐药 CMV 疾病的治疗。在过去的资助期内，该研究项目确定了导致马里巴韦耐药的病毒 UL97 和 UL27 突变，从而可以对迄今为止唯一已知对该药物产生耐药性的接受马里巴韦治疗的受试者进行及时的基因型诊断。此外，观察到的细胞培养条件对体外马瑞巴韦敏感性的影响以及细胞抗代谢物的协同作用表明，马瑞巴韦与细胞激酶抑制剂联合使用可能是有益的。在即将到来的项目期间，与马瑞巴韦和其他巨细胞病毒抗病毒药物相关的研究目标是（1）使用当代深度测序技术来追踪耐药突变的演变，从而有可能尽早发现即将出现的耐药性； (2) 通过修改对照实验室菌株的 UL128-131 基因，使它们的生长特性更类似于新鲜的临床分离株，进一步开发 CMV 耐药性的表型测定，(3) 评估已报道的细胞抗代谢物在临床用于其他适应症时的抗 CMV 活性，单独使用或与现有抗病毒药物联合使用； (4) 评估具有确定的 CMV 药物靶点的有前途的实验化合物的治疗潜力，包括效力、协同作用以及耐药性和交叉耐药性的倾向。人们期望理想的巨细胞病毒抑制疗法可能涉及具有不同作用机制的药物组合，这可以减少耐药性的发生，就像治疗其他慢性病毒感染一样。

项目成果

Recombinant phenotyping of cytomegalovirus sequence variants detected after 200 or 100 days of valganciclovir prophylaxis.

缬更昔洛韦预防 200 或 100 天后检测到的巨细胞病毒序列变异的重组表型。

• DOI: 10.1097/tp.0b013e3181fdd9d2
• 发表时间: 2010
• 期刊: Transplantation
• 影响因子: 6.2
• 作者: Chou,Sunwen;Marousek,Gail;Boivin,Guy;Goyette,Nathalie;Farhan,Mahdi;Ives,JaneAL;Elston,Robert
• 通讯作者: Elston,Robert

Analysis of Mutations in the Gene Encoding Cytomegalovirus DNA Polymerase in a Phase 2 Clinical Trial of Brincidofovir Prophylaxis.

Brincidofovir 预防的 2 期临床试验中编码巨细胞病毒 DNA 聚合酶的基因突变分析。

• DOI: 10.1093/infdis/jiw073
• 发表时间: 2016
• 期刊: The Journal of infectious diseases
• 作者: Lanier,ERandall;Foster,Scott;Brundage,Tom;Chou,Sunwen;Prichard,MarkN;Kleiboeker,Steven;Wilson,Chad;Colville,Donella;Mommeja-Marin,Herve
• 通讯作者: Mommeja-Marin,Herve