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:8332894
- 负责人:
- 金额:$ 28.62万
- 依托单位:
- 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 2016-02-28
- 项目状态:已结题
- 来源:
- 关键词:2&apos-fluoro-5-methylarabinosyluracilAddressAdoptedAdverse effectsAntineoplastic AgentsAntiviral AgentsAreaAttentionBiochemicalBiologicalBiological AssayBiologyBiopharmaceuticsCardiomyopathiesCell surfaceCellsChemicalsChromatographyClinicalCytoplasmCytosolDNA biosynthesisDNA-Directed DNA PolymeraseDataDeoxyguanosine kinaseDeveloping CountriesDevelopmentDidanosineDipyridamoleDiseaseDoseDrug KineticsDrug usageEstersFatty LiverGeneticHIVHepatitis BHepatitis B VirusHepatotoxicityHighly Active Antiretroviral TherapyInfectionKoreaLactic AcidosisLaser Scanning Confocal MicroscopyLifeLipodystrophyMalignant neoplasm of pancreasMembrane PotentialsMethodologyMitochondriaMitochondrial DNAMitoticMolecularMultiple SclerosisMyopathyNucleoside TransporterNucleosidesNucleotidesPancreatitisParentsPatientsPharmaceutical ChemistryPharmaceutical PreparationsPharmacologyPharmacotherapyPlaguePolymerasePovertyPrevention strategyProdrugsPropertyProtein IsoformsPurine NucleosidesPyrimidine NucleosidesRattusResearchReverse Transcriptase InhibitorsSolutionsStavudineTestingTherapeuticTissuesToxic effectTransgenic OrganismsUnited StatesViral CancerVirus DiseasesZidovudineacquired immunodeficiencyanaloganti-hepatitis Bbasedrug developmentfialuridinegemcitabinehuman TK2 proteininhibitor/antagonistinnovationinterdisciplinary approachinterestmitochondrial membranenovelnovel strategiesnucleoside analognucleoside kinaseoverexpressionpreemptpreventresearch studysuccesstandem mass spectrometrytooltripolyphosphateuptake
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.
PUBLIC HEALTH RELEVANCE: Highly active antiretroviral therapy (HAART) has been very useful for treating HIV/AIDS patients, but suffers from severe toxicities. The aim of this project s to develop a nucleoside transporter inhibition approach to protecting mitochondria, which get damaged by the nucleoside reverse transcriptase inhibitors present in HAART.
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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John K Buolamwini其他文献
John K Buolamwini的其他文献
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{{ truncateString('John K Buolamwini', 18)}}的其他基金
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- 资助金额:
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Studies on Probenecid Prodrugs that Protect against Mitochondrial Toxicity of Tenofovir
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10548702 - 财政年份:2022
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针对 Ryanodine 钙通道的 AD 新药发现
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- 资助金额:
$ 28.62万 - 项目类别:
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
- 批准号:
8463573 - 财政年份:2012
- 资助金额:
$ 28.62万 - 项目类别:
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
- 批准号:
8814250 - 财政年份:2012
- 资助金额:
$ 28.62万 - 项目类别:
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
- 批准号:
8628851 - 财政年份:2012
- 资助金额:
$ 28.62万 - 项目类别:
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
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8955457 - 财政年份:2012
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7756787 - 财政年份:2009
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Inhibitors of the ENT4 Adenosine Transporter for Cardioprotection
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7907749 - 财政年份:2009
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