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，猴疱疹 B 病毒 (BV) 可引起人类致命感染。 BV 是用于研究的猕猴的本土病毒，是一种潜在的 B 族生物恐怖主义制剂。人类疾病的特征是皮肤或粘膜上出现水疱，与 HSV-1 或 HSV-2 引起的疱疹病变难以区分。与很少导致中枢神经系统受累的典型 HSV 感染不同，BV 会导致迅速上升的脊髓炎和脑炎，几乎总是导致死亡。由于对处理人员的威胁以及用于生物恐怖主义的潜力，BV 感染的诊断和治疗需要改进。我们建议开发新的 HB 抗病毒靶点，包括克隆选定的 DNA 复制相关基因、表达和分离蛋白质产物、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，我们将在第一阶段计划中将重点放在胸苷激酶 (TK) 上，因为 1 型和 2 型 TK 的 HSV 抑制剂可以保护小鼠免受致命性脑炎的侵害。具体目标是：1）在真核表达载体中克隆并过表达BV TK基因，并纯化足够量的酶用于研究； 2) 全面表征BV TK的酶学特性； 3) 筛选与HSV TK具有广泛亲和力的N2-苯鸟嘌呤衍生物文库； 4) 合成新的类似物以提高效力和选择性； 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。