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（由申请方提供）：据报告猴疱疹B病毒（BV）可导致人类致死性感染。BV是研究中使用的猕猴所特有的，是一种潜在的B类生物恐怖主义制剂。人类疾病的特征是皮肤或粘膜上的水疱性出疹，与HSV-1或HSV-2引起的疱疹性病变难以区分。与典型的HSV感染很少导致中枢神经系统受累不同，BV引起快速上升的肌萎缩和脑炎，几乎总是导致死亡。由于对操作人员的威胁和用于生物恐怖主义的可能性，BV感染的诊断和治疗需要改进。我们建议开发新的抗病毒HB靶点，包括选择DNA复制相关基因的克隆，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。我们的专业知识和广泛的抑制HSV酶的化合物库将成为药物发现的起点。由于人类BV感染的病理学性质，我们将在该I期项目中将最初的努力集中在胸苷激酶（TK）上，因为HSV 1型和2型TK的抑制剂可保护小鼠免受致命性脑炎。具体目标是：1）在真核表达载体中克隆和过表达BV TK基因，并纯化足够量的用于研究的酶; 2）充分表征BV TK的酶性质; 3）筛选对HSV TK具有广泛亲和力的N2-苯基鸟嘌呤衍生物文库; 4）合成新的类似物以提高效力和选择性;和5）在细胞培养物中体外测试有前景的化合物和抗疱疹药物的抗BV活性。