Genome Targeted Inhibitors of Retroviruses

逆转录病毒基因组靶向抑制剂

• 批准号: 6554235
• 负责人: Virendra Nath PANDEY
• 金额: $ 27.21万
• 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 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6554235
• 关键词: Retroviridae; SCID mouse; antiAIDS agent; antisense nucleic acid; antiviral agents; chemical conjugate; cytotoxicity; drug delivery systems; drug screening /evaluation; genetic regulatory element; human immunodeficiency virus 1; laboratory mouse; membrane transport proteins; nucleotide analog; pharmacokinetics; pharmacology; tissue /cell culture; virus RNA; virus genetics; virus replication

DESCRIPTION (provided by applicant): The need for novel therapies that target several stages of the viral life cycle and that may not be vulnerable to the genetic flexibility of the virus are now emphasized more than ever, primarily because of the rapid emergence of drug resistant strains of HIV- 1. The target of choice is beginning to be narrowed to the 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 and averse to mutational changes. Selective intervention of the function of these regulatory regions may have profound therapeutic potential in blocking the 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-peptideconjugates will also be tested for their pharmacokinetic behaviour, 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 multiprong inhibitors of high therapeutic index. The following specific aims are proposed. Aim 1: Design and synthesis of PNA-membrane transporter peptide conjugates targeted to critical regions of HIV-1 RNA genome Aim 2: Evaluation of biodelivery and functional characterization of PNA- transporter peptide conjugates. Aim 3: Evaluation of antiviral efficacy and cytotoxicity of PNA-peptide conjugates in cell culture. Aim 4: Pharmacokinetic analysis, tissue distribution and toxicological evaluation of leading PNA-transporter peptide formulations. Aim 5: Evaluation of antiviral efficacy of PNA-peptide conjugates using SCID-hu mice model.

描述（由申请人提供）：对针对病毒生命周期几个阶段的新型疗法的需求，并且可能不容易受到病毒的遗传柔韧性的影响，现在比以往任何时候都更加强调，这主要是由于HIV-1的耐药菌株的迅速出现。 A环，Dis等对于病毒复制至关重要，并且不愿意变化。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-肽缀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，这可能有助于开发高治疗指数的有效多头抑制剂。提出了以下特定目标。 AIM 1：PNA-膜转运蛋白肽偶联物的设计和合成针对HIV-1 RNA基因组临界区域目标2：评估生物寄传和PNA-转运蛋白肽偶联物的功能表征的评估。 AIM 3：评估PNA肽在细胞培养中的抗病毒功效和细胞毒性。目标4：铅PNA转运蛋白制剂的药代动力学分析，组织分布和毒理学评估。 AIM 5：使用SCID-HU小鼠模型评估PNA肽结合物的抗病毒功效。