Boronated L-nucleotides targeted against HIV

针对 HIV 的硼化 L-核苷酸

• 批准号: 6496596
• 负责人: BARBARA RAMSAY SHAW
• 金额: $ 30.8万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6496596
• 关键词: AIDS education /prevention; DNA repair; HIV infections; RNA directed DNA polymerase; antiAIDS agent; biological transport; boron; chemical kinetics; chemical structure function; chemical synthesis; drug design /synthesis /production; enzyme inhibitors; enzyme substrate analog; host organism interaction; human immunodeficiency virus; intermolecular interaction; membrane permeability; multidrug resistance; nucleotide analog; phosphodiesterases; phosphotransferases; prodrugs; stereoisomer; tissue /cell culture; virus DNA; virus replication

DESCRIPTION (Provided by the applicant): The aim of this proposal is to create a new class of antiviral nucleotide prodrugs, which combine the potency and selectivity of L-nucleoside inhibitors for reverse transcriptase (RT) with advantages of boranophosphate substitution (in which an oxygen of the a-phosphate is replaced with a borano (BH3) group). We hypothesize that these prodrugs will have good cellular membrane permeability and, after hydrolysis of the lipophilic carriers inside the cell, would generate the (alpha-P-borano) mono-, di- and triphosphates of the corresponding nucleoside analogs. The boronated analogs are proposed to be stable to phosphodiesterases and phosphatases, yet good substrates for nucleotide kinases and selective for viral RTs. Moreover, the (alpha-P- borano) triphosphates are proposed to be effective inhibitors of the HIV-RT ATP-dependent and pyrophosphorolytic removal of nucleotide chain terminators; and a boranophosphate linkage incorporated into viral DNA is proposed to exhibit increased stability toward repair mechanisms that contribute to drug resistance. Our Specific Aims include 1) To synthesize and characterize (alpha-P-borano) analogs of potent viral replication inhibitors, including D- and L-enantiomers of 2',3'-dideoxynucleosides (2',3'-ddN), 2',3'-dideoxy- 2',3'-didehydrothymidine (d4T), 2'-deoxy-3'-thiacytidine triphosphate (3TC), and 2',3'-dideoxy-2'- fluoroarabinonucleosides (2'-FddAraN). 2) To study these boronated analogs as substrates and inhibitors of nucleoside mono- and diphosphate kinases, viral reverse transcriptases, and mammalian polymerases; to determine structure-function relationships; to select the most potent and selective polymerase chain terminators for future pharmacological studies; and to study how well boranophosphates block the repair of viral DNA and their mechanism of blockage. 3) To design new nucleotide prodrugs by conjugating selected alpha-P-boronated analogues with appropriate functional groups to facilitate their cell penetration and chemical inactivation of target molecules; and to investigate the chemical, biochemical, and biophysical properties of the analogs that are most essential for biochemical and therapeutic applications; 4) To investigate cell uptake and stability to phosphodiesterases and phosphatases; and to collaborate with other laboratories to study the activity of the new prodrugs against human viral diseases in cell culture. We anticipate that these studies will lead to better understanding of the mechanisms of nucleoside activation, viral replication, and drug resistance, and provide a basis for the rational design of more efficient and less toxic antiviral agents.

描述（由申请人提供）：该提案的目的是创建 一类新型抗病毒核苷酸前药，结合了效力和 L-核苷抑制剂对逆转录酶（RT）的选择性 硼磷酸盐取代的优点（其中的氧 a-磷酸盐被硼烷 (BH3) 基团取代）。我们假设这些 前药水解后具有良好的细胞膜渗透性 细胞内的亲脂性载体，会产生（α-P-borano） 相应核苷类似物的单磷酸、二磷酸和三磷酸。这 硼化类似物被认为对磷酸二酯酶稳定并且 磷酸酶，也是核苷酸激酶的良好底物，并且具有选择性 病毒 RT。此外，(α-P-硼烷)三磷酸酯被提议为 HIV-RT ATP 依赖性和焦磷酸去除的有效抑制剂 核苷酸链终止子；和并入硼烷磷酸键 认为病毒 DNA 中表现出更高的修复稳定性 导致耐药性的机制。我们的具体目标包括 1) 合成和表征有效病毒的（α-P-borano）类似物 复制抑制剂，包括 D- 和 L- 对映体 2',3'-二脱氧核苷 (2',3'-ddN)、2',3'-二脱氧-2',3'-二脱氢胸苷 (d4T)、2'-脱氧-3'-硫胞苷三磷酸 (3TC) 和 2',3'-二脱氧-2'- 氟阿拉伯核苷 (2'-FddAraN)。 2) 研究这些硼化类似物 核苷单磷酸和二磷酸激酶的底物和抑制剂，病毒 逆转录酶和哺乳动物聚合酶；确定 结构-功能关系；选择最有效和最有选择性的 用于未来药理学研究的聚合酶链终止剂；并学习 硼烷磷酸盐如何有效地阻止病毒 DNA 的修复及其机制 堵塞。 3) 通过缀合选定的核苷酸前药来设计新的核苷酸前药 具有适当官能团的α-P-硼化类似物，以促进 它们的细胞渗透和靶分子的化学灭活；并到 研究化学、生物化学和生物物理特性 对于生化和治疗应用来说最重要的类似物； 4) 研究细胞对磷酸二酯酶的摄取和稳定性 磷酸酶；并与其他实验室合作研究该活动 在细胞培养中对抗人类病毒性疾病的新前药。我们预计 这些研究将有助于更好地理解其机制 核苷激活、病毒复制和耐药性，并提供 为合理设计更高效、毒性更低的抗病毒药物奠定基础 代理。