NEW PHENYL NUCLEOSIDES AS ANTI-HIV AGENTS
新型苯基核苷作为抗 HIV 药物
基本信息
- 批准号:6553739
- 负责人:
- 金额:$ 7.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2002
- 资助国家:美国
- 起止时间:2002-08-01 至 2004-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION (provided by applicant): Due to the fatal nature of acquired immunodeficiency syndrome (AIDS), an intensive effort has been underway to develop new therapies or to improve existing therapies for the treatment of AIDS. Among the various structural classes of the antiviral agents investigated for the tretment of human imunodeficiency virus (HIV-1), a virus resposnsible for AIDS disease, nucleoside analogues are among the most effective. Although these nucleoside analogues, dideoxynucleosides and their carbocyclic analogs, offer great promise for the inhibition of viral replication, several shortcomings (resistance, side effects etc.) limit their use as effective therapeutic agents. Therefore, there is a critical need for the development of new potent and less toxic antiviral drugs/leads for the treatment of AIDS. Our approach to uncover new structural "lead" is to explore the nucleoside analogue structures which include a carbocycle (or various modifications thereof) wherein the conformational restrains imposed by the presence of a double bond (pi electrons) has resulted in potent antiviral activity. Therefore, in the search for a new lead as potential anti-HIV agents we hypothesize that the replacement of a dideoxynucleoside sugar ring with a rationally substituted, pi double bond rich, phenyl carbocyclic ring might mimic the required distance/electronic distribution, as in nucleosides, between the N9-puine/Nl-pyrimidine and the C5' for the binding to both target and nontarget macromolecules and this may result, at least in part, in the therapeutic as well as toxic actions of the drug. To test this hypothesis, we propose to conduct the following studies: a) design and synthesize a series of new phenylpurine and phenylpyrimidine compounds, b) conduct adenosine deaminase experiments with adenine compounds to establish the analogy with the nucleosides, and c) evaluate in-vitro activity against HIV-1. Nucleoside analogues are also effective against herpesvirus infections such as herpes simples virus (HSV), varicella zoster virus (VZV), human cytomegalovirus (HCMV), and Epstein-Barr virus (EBV), therefore we will also test these phenyl compounds against these viruses. The information gained in this project will be valuable not only in determining the mechanism of action and structure-activity relationship of these new phenyl nucleosides, but may also result in the development of a selective and potent anti-HIV agent.
描述(由申请人提供):由于获得性免疫缺陷综合征(AIDS)的致命性,人们一直在努力开发新的治疗方法或改进现有的治疗方法。在研究用于治疗人类免疫缺陷病毒(HIV-1)(一种可引起AIDS疾病的病毒)的各种结构类别的抗病毒剂中,核苷类似物是最有效的。尽管这些核苷类似物、双脱氧核苷及其碳环类似物为抑制病毒复制提供了很大的希望,但存在一些缺点(抗性、副作用等)。限制了它们作为有效治疗剂的用途。因此,迫切需要开发用于治疗AIDS的新的有效且毒性较小的抗病毒药物/先导物。我们发现新的结构“先导”的方法是探索包括碳环(或其各种修饰)的核苷类似物结构,其中由双键(π电子)的存在施加的构象限制导致有效的抗病毒活性。因此,在寻找作为潜在抗HIV剂的新先导物时,我们假设用合理取代的、富含π双键的苯基碳环取代双脱氧核苷糖环可能模拟N9-嘌呤/N1-嘧啶和C5'之间所需的距离/电子分布,如在核苷中,用于结合靶和非靶大分子,这可能导致,至少部分,药物的治疗作用和毒性作用。为了验证这一假设,我们建议进行以下研究:a)设计并合成一系列新的苯基嘌呤和苯基嘧啶化合物,B)用腺嘌呤化合物进行腺苷脱氨酶实验以建立与核苷的类似物,以及c)评估抗HIV-1的体外活性。核苷类似物也可有效对抗疱疹病毒感染,如单纯疱疹病毒(HSV)、水痘带状疱疹病毒(VZV)、人巨细胞病毒(HCMV)和EB病毒(EBV),因此我们还将测试这些苯基化合物对抗这些病毒的作用。本项目获得的信息不仅在确定这些新苯基核苷的作用机制和构效关系方面有价值,而且还可能导致开发选择性和有效的抗HIV药物。
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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Shashikant K Phadtare其他文献
Shashikant K Phadtare的其他文献
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{{ truncateString('Shashikant K Phadtare', 18)}}的其他基金
Investigation of Nucleic Acid Based Derived Tamoxifen Analogues for Breast Cancer
基于核酸的他莫昔芬类似物治疗乳腺癌的研究
- 批准号:
7895637 - 财政年份:2008
- 资助金额:
$ 7.26万 - 项目类别:
Investigation of Nucleic Acid Based Derived Tamoxifen Analogues for Breast Cancer
基于核酸的他莫昔芬类似物治疗乳腺癌的研究
- 批准号:
7667285 - 财政年份:2008
- 资助金额:
$ 7.26万 - 项目类别:
Investigation of Nucleic Acid Based Derived Tamoxifen Analogues for Breast Cancer
基于核酸的他莫昔芬类似物治疗乳腺癌的研究
- 批准号:
8112691 - 财政年份:2008
- 资助金额:
$ 7.26万 - 项目类别:
Investigation of Nucleic Acid Based Derived Tamoxifen Analogues for Breast Cancer
基于核酸的他莫昔芬类似物治疗乳腺癌的研究
- 批准号:
7499196 - 财政年份:2008
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用于癌症化疗的芳香族奈普兰菌素类似物
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6727045 - 财政年份:2004
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AMIFOSTINE ESTERS FOR CYTOTOXIC CHEMOPROTECTION
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6581858 - 财政年份:2002
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6450667 - 财政年份:2001
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AMIFOSTINE ESTERS FOR CYTOTOXIC CHEMOPROTECTION
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6478793 - 财政年份:2001
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6318328 - 财政年份:2000
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