Structure activity and structure property relationships for novel anti-HIV agents

新型抗HIV药物的结构活性和结构性质关系

基本信息

  • 批准号:
    8777085
  • 负责人:
  • 金额:
    $ 4.14万
  • 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:
    2012-12-01 至 2015-08-21
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Reverse transcriptase (RT) is an essential enzyme that copies the viral RNA genome into double stranded DNA via polymerization, a process required for HIV-1 infection. Several enzymes in HIV-1, including RT, are drug targets for highly active antiretroviral therapies (HAART). Non-nucleoside and non-nucleotide RT inhibitors (NNRTIs) are therapeutics prescribed in combination with 3-4 additional antiviral agents that work synergistically to induce viral load suppression in infected patients. Currently, there are fie FDA approved NNRTIs targeting RT, which include nevirapine, delaviridine, efavirenz, etravirine, and rilpivirine. However, there are several limitations to current NNRTIs such as resistance and toxicity issues from long-term usage. The design and development of new NNRTIs with improved resistance and safety profiles is crucial to overcome HIV-1 treatment failure. Over the last few years, we have developed several new compounds as potential NNRTIs using a combination of mechanistic studies, computational chemistry, and structure-based drug design. We have recently designed an NNRTI compound that is active against HIV-1 and has a therapeutic index of 180,000 for cellular toxicity. With an EC50 of 55 pM, this compound emerges as the most potent antiviral agent targeting HIV-1 to date. In order to optimize these compounds into potential drug candidates, this proposal aims to develop structure activity relationships (SAR) and structure property relationships (SPR). Pre-steady state kinetics will determine binding affinity measurements for leading NNRTI compounds and the RT enzyme. In addition to binding affinities, co-crystallization of leading NNRTIs and the RT enzyme will provide a structural interpretation for enzyme-inhibitor interactions and SAR. A series of in vitro analytical and pharmacological techniques will be used to determine SPR for leading compounds. Structure property measurements to be determined include lipophilicity, kinetic solubility, permeability, and metabolic stability. The combination of both SAR and SPR for leading NNRTI compounds will prioritize future development and provide structural information for rational drug design of efficacious NNRTIs.
描述(由申请方提供):逆转录酶(RT)是一种通过聚合将病毒RNA基因组复制成双链DNA的必需酶,这是HIV-1感染所需的过程。HIV-1中的几种酶,包括RT,是高效抗逆转录病毒疗法(HAART)的药物靶点。非核苷和非核苷酸RT抑制剂(NNRTI)是与3 - 4种额外的抗病毒药剂联合使用的治疗药物,这些抗病毒药剂协同作用,以诱导感染患者的病毒载量抑制。目前,有五种FDA批准的靶向RT的非核苷类逆转录酶抑制剂,包括奈韦拉平、地拉韦啶、依法韦仑、依曲韦林和利匹韦林。然而,目前的NNRTI有几个局限性,如长期使用的耐药性和毒性问题。设计和开发具有改善的耐药性和安全性的新NNRTI对于克服HIV-1治疗失败至关重要。在过去的几年里,我们已经开发了几种新的化合物作为潜在的NNRTI使用的机制研究,计算化学和基于结构的药物设计的组合。我们最近设计了一种NNRTI化合物,该化合物对HIV-1具有活性,细胞毒性治疗指数为180,000。该化合物的EC50为55 pM,是迄今为止针对HIV-1的最有效的抗病毒剂。为了优化这些化合物成为潜在的候选药物,本建议旨在发展构效关系(SAR)和结构性质关系(SPR)。预稳态动力学将确定主要NNRTI化合物和RT酶的结合亲和力测量。除了结合亲和力外,主要NNRTI和RT酶的共结晶将为酶-抑制剂相互作用和SAR提供结构解释。一系列体外分析和药理学技术将用于确定先导化合物的SPR。待测定的结构性质测量包括亲脂性、动力学溶解度、渗透性和代谢稳定性。对于主要的NNRTI化合物,SAR和SPR的组合将优先考虑未来的开发,并为有效的NNRTI的合理药物设计提供结构信息。

项目成果

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Kathleen Mary Frey其他文献

Kathleen Mary Frey的其他文献

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{{ truncateString('Kathleen Mary Frey', 18)}}的其他基金

Structure activity and structure property relationships for novel anti-HIV agents
新型抗HIV药物的结构活性和结构性质关系
  • 批准号:
    8466077
  • 财政年份:
    2012
  • 资助金额:
    $ 4.14万
  • 项目类别:
Structure activity and structure property relationships for novel anti-HIV agents
新型抗HIV药物的结构活性和结构性质关系
  • 批准号:
    8588784
  • 财政年份:
    2012
  • 资助金额:
    $ 4.14万
  • 项目类别:

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