Genome Targeted Inhibitors of Retroviruses

逆转录病毒基因组靶向抑制剂

• 批准号: 6657175
• 负责人: Virendra Nath PANDEY
• 金额: $ 19.44万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6657175
• 关键词: Retroviridae; SCID mouse; amides; antiAIDS agent; antigenic peptide transporter; antiviral agents; cell line; clone cells; drug design /synthesis /production; drug screening /evaluation; drug vehicle; flow cytometry; gene targeting; green fluorescent proteins; growth inhibitors; high performance liquid chromatography; human immunodeficiency virus 1; mass spectrometry; matrix assisted laser desorption ionization; membrane transport proteins; nucleotide analog; pharmacokinetics; tissue /cell culture; ultraviolet spectrometry; virus genetics; virus replication

DESCRIPTION (provided by applicant): The major drawback to current and-ADS therapy is the emergence of drug resistant mutants of HIV- 1. In the quest for novel HIV- 1 specific inhibitors, our strategy has been to target the conserved non-translated 5' region of the viral genome that contains multiple regulatory elements such as TAR, PBS, A-loop, DIS etc which are critical for viral replication. Selective intervention of the function of these regulatory regions may have profound therapeutic potential in blocking viral infection. We have identified a number of leading polyamide nucleotide analogs (PNA) which can successfully block the function of these targets in vitro. The major thrust of this proposal is to conjugate these leading PNAs with a number of membrane transporting peptides in order to identify the most efficient biodelivery system thus enhancing the functional efficacy of these compounds. Each PNA-peptide conjugate will be examined in-depth with respect to its uptake kinetics, functional efficacy, cytotoxicity and antiviral activity in cell cultures. The leading PNA-peptide conjugates will also be tested for their pharmacokinetic behavior, tissue distribution and toxicological properties in animal models. This will be followed by subjecting these compounds to pre-clinical trial on hu-SCID mice model reconstructed with human PBL. These studies will provide invaluable information on this class of compounds, which may help in the development of effective multi-pronged inhibitors of high therapeutic index. The following specific aims are proposed. (1) To design and synthesize potential PNA - MTD peptide conjugates targeted to the critical regions of HIV- 1 RNA genome. (2) To evaluate the biodelivery and functional efficacy of PNA- transporter peptide conjugates.; (3) To evaluate the antiviral efficacy and cytotoxicity of PNA-peptide conjugates in cell culture. (4) To carry out pharmacokinetic studies, tissue distribution analysis, and toxicological evaluation of leading PNA-transporter peptide formulations.; (5) To determine the immune response of potential PNA-MTD peptide conjugates.; (6) To evaluate the antiviral efficacy of PNA-peptide conjugates using SCID-hu mice model.

描述（由申请人提供）： 当前和ADS疗法的主要缺点是HIV-1的耐药突变体的出现。在寻求新颖的HIV-1特异性抑制剂时，我们的策略是针对保守的非翻译5'病毒基因组的5'区域，该区域包括包含TAR，PBS，PBS，Aloop，A-loop，a-loop，dis等对病毒性重复作用的多个调节元素的病毒基因组。这些调节区域功能的选择性干预可能在阻断病毒感染方面具有深远的治疗潜力。我们已经确定了许多铅的聚酰胺核苷酸类似物（PNA），这些核苷酸类似物（PNA）可以成功地阻断这些靶标的体外功能。该提案的主要目的是将这些领先的PNA与许多运输肽的膜结合起来，以识别最有效的生物传递系统，从而增强这些化合物的功能功效。每种PNA肽结合物将在细胞培养物中的摄取动力学，功能疗效，细胞毒性和抗病毒活性方面进行深入研究。在动物模型中，领先的PNA肽结合物还将测试其药代动力学行为，组织分布和毒理学特性。随后将对这些化合物进行对使用人PBL重建的HU-SCID小鼠模型的临床前试验。这些研究将提供有关此类化合物的宝贵信息，这可能有助于开发有效的高治疗指数的多管齐下抑制剂。提出了以下特定目标。 （1）设计和合成潜在的PNA -MTD肽结合物，该肽偶联物靶向HIV -1 RNA基因组的关键区域。 （2）评估PNA-转运蛋白肽结合物的生物传递和功能功效。 （3）评估PNA肽偶联物在细胞培养中的抗病毒功效和细胞毒性。 （4）进行药代动力学研究，组织分布分析和毒理学评估。 （5）确定潜在的PNA-MTD肽结合物的免疫反应。 （6）使用SCID-HU小鼠模型评估PNA肽结合物的抗病毒功效。