NUCLEOSIDES WITH DUAL ANTIHIV AND HBV ACTIVITY

具有双重抗 HIV 和 HBV 活性的核苷

• 批准号: 2432844
• 负责人: Raymond Felix Schinazi
• 金额: $ 15.46万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2432844
• 关键词: 2'3' dideoxycytidine; 2'3' dideoxyinosine; 2'3' dideoxynucleoside; 5 fluorodeoxycytidine; antiAIDS agent; antiviral agents; drug interactions; drug screening /evaluation; hepatitis B virus group; human immunodeficiency virus 1; nucleoside triphosphate; pharmacokinetics; tissue /cell culture

DESCRIPTION (Adapted from the Investigator's Abstract): The overall goal of this Interactive Research Project Grant (IRPG) is to develop new antiviral nucleosides, for use in combination against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infections. As a first step, the applicant wishes to focus on a new compound discovered in his laboratory that has dual potent and selective activity against HIV/HBV. b-D-2',3'-Didehydro-2',3'-dideoxy-5-fluorocytidine (D-D4FC) and related molecules will be studied extensively at the biochemical, virological, molecular therapeutical, and pharmacological level in cell-free and cellular systems. The activity of D-D4FC will be tested against a panel of well characterized clinical isolates of HIV in primary human lymphocytes. HIV-1 resistant to other nucleoside analogs will also be tested for cross-resistance to D-D4FC. Based on the cross-resistance pattern, D-D4FC will be evaluated in double and triple combinations with AZT, 3TC, (-)-FTC, d4T, ddI, ddC, a protease inhibitor such as indinavir, and a nonnucleoside reverse transcriptase inhibitor, such as nevirapine. Moreover, the relative rate for the emergence of resistance to D-D4FC will be determined and compared with 3TC [or (-)-FTC] and AZT. D-D4FC is currently being evaluated in a woodchuck hepatitis virus model by the NIAID. This application proposes to conduct combination studies of D-D4FC with 3TC, DAPD and (-)-FTC, compounds with dual anti-HIV and anti-HBV activity in HBV transfected cells. The potency and selectivity of the 5'-triphosphate of D-D4FC will be compared to the L-enantiomer and related nucleotides by studying the inhibition of the HIV-1 reverse transcriptase, the HBV DNA polymerase, and several human DNA polymerases. Radiolabeled D-D4FC and L-D4FC will be synthesized and their cellular pharmacology will be determined in order to gain insight into their different biological properties.

描述（根据调查员的摘要进行了改编）： 这项互动研究项目赠款（IRPG）是开发新的抗病毒 核苷，用于针对人免疫缺陷病毒的组合 （HIV）和丙型肝炎病毒（HBV）感染。作为第一步， 申请人希望专注于他的实验室发现的新化合物 这具有针对HIV/HBV的双重有效和选择性活动。 B-D-2'，3'-二氢-2'，3'-二氧 - 5-氟环丁胺（D-D4FC）及相关 分子将在生化，病毒学， 无细胞和细胞的分子治疗和药理水平 系统。 D-D4FC的活性将针对井进行测试 在原发性人淋巴细胞中，艾滋病毒的临床分离株。 HIV-1 对其他核苷类似物的抗性也将进行测试 D-D4FC的交叉抗性。基于跨耐药模式D-D4FC 将以AZT，3TC，（ - ）-FTC的双重组合和三重组合评估 D4T，DDI，DDC，一种蛋白酶抑制剂，例如indinavir和非核苷 逆转录酶抑制剂，例如奈韦拉平。而且，亲戚 将确定抗D-D4FC的抗性的速率，并 与3TC [或（ - ） - FTC]和AZT相比。目前正在评估D-D4FC 在NIAID的Woodchuck肝炎病毒模型中。此应用程序 建议对D-D4FC与3TC，DAPD和 （ - ） - FTC，HBV中具有双抗HIV和抗HBV活性的化合物 转染的细胞。 5'三磷酸盐的效力和选择性 D-D4FC将与L-偏南元素和相关核苷酸进行比较 研究HIV-1逆转录酶HBV DNA的抑制作用 聚合酶和几种人DNA聚合酶。放射标记的D-D4FC和 L-D4FC将合成，其细胞药理学将是 确定要深入了解其不同的生物学 特性。