Genome Targeted Inhibitors of Retroviruses

逆转录病毒基因组靶向抑制剂

• 批准号: 6842205
• 负责人: Virendra Nath PANDEY
• 金额: $ 38.88万
• 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/6842205
• 关键词: Genome; Targeted; Inhibitors; Retroviruses

Principal InvestigatodProgram Director (Last, first, middle): Pandey_ V. N, DESCRIPTION. State the application's broad, long-term objectives and specific aims,making reference to the health relatednessof the project. Describe concisely the research design and methods for achieving these goals. Avoid summaries of past accomplishments and the use of the first person. This description is meant to serve as a succinct and accurate description of the proposed workwhen separated from the application. If the application is funded, this description, as is, will become public information. Therefore, do not include proprietary/confidential information. D O N OT E XC E E D T H E S P A C E P RO Vl D E D. 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 inhibitcrs, our strategy has been to target the conserved non-translated5' 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 therapeuticpotential 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 multiprong inhibitors of high therapeutic index. The following specific aims are proposed. Aim 1: To design and synthesize potential PNA - MTD peptide conjugates targeted to the critical regions of HIV- 1 RNA genome. Aim 2: To evaluate the biodelivery and functional efficacy of PNA- transporter peptide conjugates. Aim 3: To evaluate the antiviral efficacy and cytotoxicity of PNA-peptide conjugates in cell culture. Aim 4: To carry out pharmacokinetic studies, tissue distribution analysis, and toxicological evaluation of leading PNA-transporter peptide formulations. Aim 5: To determine the immune response of potential PNA-MTD peptide conjugates. Aim 6: To evaluate the antiviral efficacy of PNA-peptide conjugates using SCID-hu mice model. PERFORMANCE SITE ========================================Section End===========================================

主要研究项目负责人（最后，第一，中间）：Pandey_V. N，描述。说明申请的广泛、长期目标和具体目标，并提及项目的健康相关性。简要描述研究设计和实现这些目标的方法。避免总结过去的成就和使用第一人称。本说明书旨在作为与申请分开的拟议工作的简洁和准确的描述。如果申请获得资助，此描述将成为公共信息。因此，不包括专有/机密信息。D O O OT E XC E E D T H E S P A C E P RO VI D E D.目前抗-ADS治疗的主要缺点是HIV- 1耐药突变体的出现。在寻找新的HIV- 1特异性转录因子的过程中，我们的策略是靶向病毒基因组的保守的非转录的5 '区域，该区域包含对病毒复制至关重要的多个调节元件，如TAR、PBS、A环、DIS等。选择性干预这些调控区域的功能可能在阻断病毒感染方面具有深远的治疗潜力。我们已经确定了一些领先的聚酰胺核苷酸类似物（PNA），可以成功地阻止这些目标在体外的功能。该建议的主要目的是将这些主要的PNA与许多膜转运肽缀合，以鉴定最有效的生物递送系统，从而增强这些化合物的功能功效。将深入检查每种PNA-肽缀合物在细胞培养物中的摄取动力学、功能功效、细胞毒性和抗病毒活性。还将在动物模型中测试主要PNA-肽缀合物的药代动力学行为、组织分布和毒理学性质。随后将在用人PBL重建的hu-SCID小鼠模型上对这些化合物进行临床前试验。这些研究将提供关于这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方面抑制剂。提出了以下具体目标。目的1：设计合成靶向HIV- 1 RNA关键区域的肽段偶联物。目的2：评价肽核酸转运蛋白偶联物的生物释放和功能性.目的3：研究PNA-肽偶联物在细胞培养中的抗病毒效果和细胞毒性。目标4：开展主要PNA转运蛋白肽制剂的药代动力学研究、组织分布分析和毒理学评价。目的5：确定潜在PNA-MTD肽缀合物的免疫应答。目的6：利用SCID-hu小鼠模型评价PNA-肽偶联物的抗病毒效果。性能现场=