Antiviral Drugs for Treatment of Herpes B Infections

用于治疗 B 型疱疹感染的抗病毒药物

• 批准号: 6646073
• 负责人: George E Wright
• 金额: $ 25.37万
• 依托单位: GLSYNTHESIS, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-05-15 至 2005-05-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6646073
• 关键词: Cercopithecid herpesvirus 1; antiviral agents; drug design /synthesis /production; drug screening /evaluation; enzyme activity; expression cloning; genetic library; thymidine kinase; tissue /cell culture; transfection; transfection /expression vector

DESCRIPTION (provided by applicant): Monkey Herpes B virus (BV) has been reported to cause lethal infections in humans. BV is indigenous to macaque monkeys used in research, and is a potential group B bioterrorism agent. Human disease is characterized by vesicular eruptions on the skin or mucous membranes that are indistinguishable from herpetic lesions caused by HSV-1 or HSV-2. Unlike typical HSV infections that rarely lead to central nervous system involvement, BV causes a rapidly ascending myelitis and encephalitis that almost always leads to death. Because of the threat to handlers and potential for use in bioterrorism, diagnosis and treatment of BV infection need to be improved. We propose to develop new antiviral targets for HB involving cloning of selected DNA replication-related genes, expression and isolation of the protein products, and characterization of the substrate and inhibitor properties of the enzymes. Our expertise and extensive libraries of compounds that inhibit the HSV enzymes will be the starting point in drug discovery. Because of the nature of the pathology of BV infection in humans, we will focus initial efforts in this phase I program on thymidine kinase (TK), because inhibitors of the HSV types 1 and 2 TKs protect mice from lethal encephalitis. The specific aims are: 1) to clone and overexpress the BV TK gene in eukaryotic expression vectors, and purify sufficient quantities of the enzyme for study; 2) to fully characterize the enzymatic properties of BV TK; 3) to screen a library of N2-phenylguanine derivatives that have a wide range of affinities for the HSV TKs; 4) to synthesize new analogs to improve potency and selectivity; and 5) to test promising compounds and antiherpes drugs in vitro for anti-BV activity in cell cultures.

描述（由申请人提供）：据报道，猴子B病毒（BV）会引起人类致命感染。 BV是研究中使用的猕猴的土著，并且是B组生物恐怖剂。人类疾病的特征是皮肤上的囊泡爆发或粘膜与HSV-1或HSV-2引起的疱疹病变无法区分的粘膜。与很少导致中枢神经系统受累的典型HSV感染不同，BV会引起迅速上升的骨髓炎和脑炎，几乎总是导致死亡。由于对处理者的威胁和在生物恐怖主义中使用的潜力，因此需要改善对BV感染的诊断和治疗。我们建议开发新的抗病毒靶标，以涉及涉及选定的DNA复制基因的克隆，蛋白质产物的表达和分离，以及酶的底物和抑制剂特性的表征。我们抑制HSV酶的化合物的专业知识和广泛的图书馆将是药物发现的起点。由于人类BV感染的病理性质，因此我们将在胸苷激酶（TK）的I阶段计划中重点努力，因为HSV类型1和2 TKS的抑制剂可保护小鼠免受致命性脑炎的影响。具体目的是：1）在真核表达载体中克隆和过表达BV TK基因，并净化足够数量的酶进行研究； 2）充分表征BV TK的酶特性； 3）筛选一个N2-苯基鸟嘌呤衍生物的库，这些衍生物具有广泛的HSV TKS； 4）合成新的类似物以提高效力和选择性； 5）在体外测试有希望的化合物和抗抗抑制剂药物在细胞培养物中的抗BV活性。