Genome Targeted Inhibitors of Retroviruses

首席调查项目主任(最后、第一、中间)：Pandey_V.N，描述。说明应用程序的广泛、长期目标和具体目标，并参考该项目与健康相关的内容。简明扼要地描述实现这些目标的研究设计和方法。避免总结过去的成就和使用第一人称。此描述的目的是在与应用程序分离时，作为对拟议工作的简洁而准确的描述。如果申请得到资助，这一描述将成为公开信息。因此，不包括专有/机密信息。目前和-ADS治疗的主要缺点是出现HIV-1耐药突变株。在寻找新的HIV-1特异性抑制剂的过程中，我们的策略是瞄准病毒基因组中保守的非翻译5‘区，该区域包含多种对病毒复制至关重要的调控元件，如TAR、PBS、A-loop、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)，它们可以在体外成功地阻断这些靶标的功能。这一建议的主要目的是将这些主要的PNA与一些膜转运肽结合，以确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。每个PNA-肽结合物都将在细胞培养中就其摄取动力学、功能功效、细胞毒性和抗病毒活性进行深入研究。领先的PNA-肽结合物还将在动物模型中测试其药代动力学行为、组织分布和毒理学特性。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，这可能有助于开发有效的多用途高治疗指数抑制剂。提出了以下具体目标。目的1：设计并合成针对HIV-1RNA基因组关键区域的潜在PNA-MTD多肽结合物。目的：评价PNA-转运蛋白多肽结合物的生物利用度和功能效果。目的：评价PNA-肽结合物在细胞培养中的抗病毒效果和细胞毒性。目的：对主要的PNA转运蛋白多肽制剂进行药代动力学研究、组织分布分析和毒理学评价。目的：测定潜在的PNA-MTD多肽结合物的免疫应答。目的：利用SCID-Hu小鼠模型评价PNA-多肽结合物的抗病毒作用。表演网站========================================Section End===========================================

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===========================================