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A Targeted Preemptive Approach to Addressing Mitochondrial Toxicity of Nucleoside

解决核苷线粒体毒性的有针对性的先发制人方法

基本信息

批准号：
8814250
负责人：
John K Buolamwini
金额：
$ 24.42万
依托单位：
ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-05-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8814250
关键词：
Address Adopted Adverse effects Antineoplastic Agents Antiviral Agents Area Attention Biochemical Biological Biological Assay Biology Biopharmaceutics Cardiomyopathies Cell surface Cells Chemicals Chromatography Clinical Cytoplasm Cytosol DNA biosynthesis DNA-Directed DNA Polymerase Data Deoxyguanosine kinase Developing Countries Development Didanosine Dipyridamole Disease Dose Drug Kinetics Drug usage Esters Fatty Liver Genetic HIV HepG2 Hepatitis B Hepatitis B Virus Hepatotoxicity Highly Active Antiretroviral Therapy Infection Korea Lactic Acidosis Laser Scanning Confocal Microscopy Life Lipodystrophy Malignant neoplasm of pancreas Membrane Potentials Methodology Mitochondria Mitochondrial DNA Mitotic Molecular Multiple Sclerosis Myopathy Nucleoside Transporter Nucleosides Nucleotides Pancreatitis Parents Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Plague Polymerase Poverty Prevention strategy Prodrugs Property Protein Isoforms Purine Nucleosides Pyrimidine Nucleosides Rattus Research Reverse Transcriptase Inhibitors Solutions Stavudine Testing Therapeutic Tissues Toxic effect Transgenic Organisms United States Viral Cancer Virus Diseases Zidovudine acquired immunodeficiency analog anti-hepatitis B base drug development fialuridine gemcitabine human TK2 protein inhibitor/antagonist innovation interdisciplinary approach interest mitochondrial membrane novel novel strategies nucleoside analog nucleoside kinase overexpression preempt prevent research study success tandem mass spectrometry tool tripolyphosphate uptake

项目摘要

DESCRIPTION (provided by applicant): Although the introduction of highly active antiretroviral therapy (HAART) targeting the human immunodeficiency virus (HIV) revolutionized acquired immunodeficiency disease (AIDS) therapy, nucleoside reverse transcriptase inhibitors (NRTIs) that are a cornerstone of HAART cocktails have been found to cause severe mitochondrial toxicities that have limited their use. NRTIs cause toxicity by inhibiting mitochondrial DNA (mtDNA) synthesis through inhibition of polymerase g (Pol g), which is responsible for mtDNA synthesis. Although anti-HIV NRTIs have drawn the most attention to nucleoside drug-induced mitochondrial toxicity, this toxicity has also been seen with other antiviral nucleoside drugs such as fialuridine (FIAU) and clevudine (L-FMAU) that were being developed to treat hepatitis B (HBV) infections, and gemcitabine, the drug of choice for the treatment of pancreatic cancer. Moreover, the problem is likely to become more widespread as nucleoside drugs are used outside the antiviral and anticancer fields to disease areas such as multiple sclerosis. Unfortunately, there is no current proven general treatment of prevention strategy for nucleoside drug-induced mitochondrial toxicity. Thus, the development of innovative approaches to preempt or treat mitochondrial toxicity will be an important advance in the field of nucleoside drug therapy. NRTI triphosphates, the metabolites that inhibit Pol g can be synthesized inside mitochondria from imported NRTIs from the cytosol. Imported nucleosides are sequentially phosphorylated starting with rate-limiting monophosphorylation by mitochondrial-specific thymidine kinase 2 (TK-2) and/or deoxyguanosine kinase (dGK). Mitochondrial membrane nucleoside transporters (NTs) import NRTIs from the cytoplasm. The NT isoforms that have been implicated in mitochondrial nucleoside uptake are the equilibrative nucleoside transporters (ENTs), particularly ENT1 and ENT3. The transgenic overexpression of ENTs has been shown to enhance the mitochondrial toxicity of the former anti-hepatitis B nucleoside drug fialuridine (FIAU) and the NRTI AIDS drug AZT. We have obtained preliminary data showing that a prodrug approach could be used to protect against NRTI-induced mitochondrial toxicity; and we will test that hypothesis by pursuing the following specific aims: 1) synthesize and characterize novel prodrugs for lack of NT inhibition and cellular release of active drug, 2) evaluate the abiliy of prodrugs to protect mitochondria from the toxicity of nucleoside analog drugs, and 3) study biopharmaceutic and pharmacokinetic properties of selected prodrugs and their influence on the pharmacokinetics of nucleoside drugs of interest. A multidisciplinary approach integrating synthetic medicinal chemistry, biochemical and molecular biological assays, laser scanning confocal microscopy, chromatography and tandem mass spectrometry will be employed. The success of the project will confirm the possibility of protecting against nucleoside analog mitochondrial toxicity through the inhibition of nucleoside transporters, as an innovative general preemptive means of protection against toxicities of anti-HIV NRTIs and other nucleoside drugs like the anticancer nucleoside analog gemcitabine, which is associated with rare but potentially fatal liver toxicity and myopathy. Novel research tools will also be developed.

描述（由申请人提供）：尽管针对人类免疫缺陷病毒（HIV）的高活性抗逆转录病毒疗法（HAART）的引入彻底改变了获得性免疫缺陷病（AIDS）的治疗方法，但作为HAART鸡尾酒疗法基石的核苷类逆转录酶抑制剂（NRTIs）已被发现会导致严重的线粒体毒性，限制了其使用。NRTIs通过抑制负责mtDNA合成的聚合酶g （Pol g）来抑制线粒体DNA （mtDNA）的合成，从而引起毒性。尽管抗hiv nrti引起了核苷类药物引起的线粒体毒性的关注，但这种毒性也见于其他抗病毒核苷类药物，如