Development of Novel Nucleoside Triphosphate Prodrugs

新型核苷三磷酸前药的开发

基本信息

批准号：
8039049
负责人：
ROBERT D KUCHTA
金额：
$ 20.31万
依托单位：
UNIVERSITY OF COLORADO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-21 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8039049
关键词：
Acyclovir Address Adverse effects Affect Anti-HIV Agents Antineoplastic Agents Antiviral Agents Biochemical Bypass Cell Line Cells Charge Cytarabine Cytosol DNA DNA-Directed DNA Polymerase DNA-Directed RNA Polymerase Deoxycytidine Kinase Development Enzymes Excision Exhibits Goals HIV HIV Infections Herpesvirus 1 Infection Lead Malignant Neoplasms Masks Methods Modification Normal Cell Nucleosides Nucleotides Oxygen Phosphoglycerate Kinase Phosphorylation Phosphotransferases Play Polymerase Problem Solving Process Prodrugs Property RNA RNA-Directed DNA Polymerase Relative (related person)Ribonucleosides Role Safety Scheme Specificity Testing Therapeutic Thymidine Kinase Viral Viral Cancer Virus Virus Diseases Work Zalcitabine Zidovudine acyclovir triphosphate analog anti-cancer therapeutic base chemical property chemical synthesis design flexibility gemcitabine inhibitor/antagonist inorganic phosphate interest novel nucleoside analog nucleoside kinase nucleoside triphosphate sugar tissue culture tripolyphosphate

项目摘要

DESCRIPTION (provided by applicant): The goal of the proposed work is to develop a novel method for delivering biologically interesting nucleoside triphosphates into cells that would bypass the (deoxy)nucleoside, (d)NMP and NDP kinases normally needed to convert nucleosides into nucleoside triphosphates. Nucleosides are an extraordinarily important class of antiviral and anticancer therapeutics. The biologically active form of nucleosides is generally the nucleoside triphosphate, and their activity results from inhibition of DNA or RNA polymerases and/or incorporation into DNA or RNA. Unfortunately, the kinases involved in converting a nucleoside to a nucleoside triphosphate generally exhibit substantial specificity towards both the base and sugar. Consequently, a large number of potentially therapeutic nucleosides are completely useless as polymerase inhibitors because they are not converted to the biochemically active triphosphate. To overcome this problem, a novel prodrug approach will be developed that will allow for the delivery of masked nucleoside triphosphate mimics into cells. Upon entering the cells, unmasking will be initiated by cellular enzymes to liberate the nucleoside triphosphate mimic. In these initial studies, HIV reverse transcriptase will be targeted since a number of anti-HIV drugs are not efficiently phosphorylated by cellular kinases and reverse transcriptase readily tolerates modification of the triphosphate. The methods developed, however, are designed to be broadly applicable to virtually any nucleoside triphosphate and most DNA (or RNA) polymerases. To accomplish this goal, two specific aims will be addressed: (1) Develop highly efficient and robust syntheses of nucleoside triphosphate prodrugs and characterize their chemical properties. (2) Optimize the biochemical properties of the prodrugs so that they efficiently enter cells and are unmasked to generate the triphosphate. The results of these studies will be used to direct the synthesis of prodrugs of 3'- azido-3'-deoxythymidine triphosphate that will be tested as inhibitors of HIV. PUBLIC HEALTH RELEVANCE: Nucleoside analogues have proven to be an extremely powerful class of both anti-cancer and anti- viral chemotherapeutics. However, the specificity of the kinases required for converting a nucleoside into the medically relevant nucleoside triphosphate often limits the utility of potentially interesting nucleosides. Having a generally applicable method for directly delivering nucleoside triphosphate mimics into cells could greatly expand the utility of nucleoside analogues and potentially lead to new treatments of both viral infections and cancer.

描述（由申请人提供）：拟议工作的目标是开发一种新方法，将具有生物学意义的三磷酸核苷递送到细胞中，该方法将绕过通常将核苷转化为核苷所需的（脱氧）核苷、(d)NMP 和 NDP 激酶三磷酸盐。核苷是一类极其重要的抗病毒和抗癌治疗药物。核苷的生物活性形式通常是三磷酸核苷，其活性来自于抑制DNA或RNA聚合酶和/或掺入DNA或RNA。不幸的是，参与将核苷转化为核苷三磷酸的激酶通常对碱基和糖都表现出显着的特异性。因此，大量具有潜在治疗作用的核苷作为聚合酶抑制剂是完全无用的，因为它们没有转化为具有生化活性的三磷酸。为了克服这个问题，将开发一种新的前药方法，该方法将允许将掩蔽的核苷三磷酸模拟物递送到细胞中。进入细胞后，细胞酶将启动揭露，释放三磷酸核苷模拟物。在这些初步研究中，HIV逆转录酶将成为目标，因为许多抗HIV药物不能被细胞激酶有效磷酸化，并且逆转录酶容易耐受三磷酸的修饰。然而，所开发的方法旨在广泛适用于几乎任何三磷酸核苷和大多数 DNA（或 RNA）聚合酶。为了实现这一目标，将解决两个具体目标：（1）开发高效、稳健的三磷酸核苷前药合成方法并表征其化学性质。 (2)优化前药的生化特性，使其有效进入细胞并生成三磷酸。这些研究的结果将用于指导 3'-叠氮基-3'-脱氧胸苷三磷酸前药的合成，该前药将作为 HIV 抑制剂进行测试。公共卫生相关性：核苷类似物已被证明是一类极其强大的抗癌和抗病毒化疗药物。然而，将核苷转化为医学相关的三磷酸核苷所需的激酶的特异性通常限制了潜在有趣的核苷的效用。拥有一种普遍适用的方法将核苷三磷酸模拟物直接递送到细胞中可以极大地扩展核苷类似物的用途，并有可能带来病毒感染和癌症的新治疗方法。