STRUCTURE BASED DESIGNS OF CELL PENETRATING PEPTIDES

基于结构的细胞穿透肽设计

• 批准号: 7723392
• 负责人: Sandhya Kortagere
• 金额: $ 0.05万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7723392
• 关键词: Address; Affinity; Biological; Blood - brain barrier anatomy; Cells; Clinical; Computer Retrieval of Information on Scientific Projects Database; Diagnostic; Drug Delivery Systems; Drug Design; Endocytosis; Funding; Grant; In Vitro; Institution; Lead; Lipid Bilayers; Mediating; Membrane; Numbers; Peptides; Pharmaceutical Preparations; Process; Property; Proteins; Research; Research Personnel; Resources; Role; Source; Staging; Structure; Structure-Activity Relationship; Technology; Testing; Therapeutic; Translations; United States National Institutes of Health; antimicrobial peptide; base; design; high throughput screening; novel; receptor

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Advances in drug design and high throughput screening technologies have led to the design of a number of therapeutics and diagnostic agents that target various intracellular molecules. However, biodelivery of these drugs and diagnostic agents to their right target remains a significant challenge. Nearly 30% of all early stage lead molecules that have high affinity to the target determined by in-vitro testing do not make it to clinical trails due to their inability to reach their intended targets (Lipinski, 2001). Similarly transporting hydrophilic molecules across the blood brain barrier remains an equally challenging problem. Hence, there is a growing effort to develop novel molecules that can pass through biological membranes and can be used as vehicles for efficient drug delivery. During the past decade, several cell penetrating peptides (CPPs) that enable the intracellular delivery of drugs have been identified. These peptides can be derived from proteins and are called protein transduction domains which are known to efficiently transverse biological membranes. Although the actual mechanism of action is not known, it is widely understood that the process is receptor and transporter independent (Derossi et al., 1996). The translocation is also not endocytosis mediated and may target the lipid bilayer directly (Frankel et al., 1988 and Plank et al., 1998). Thus a direct contact between the translocating peptide and the lipid bilayer needs to be established. Experimental observations have noted that during the peptide translocation process, the peptide induces membrane reorganization due to pore formation, fusion and also temporary destabilizations (Mangoni et al., 1996). The present project will focus on the structural mechanisms involved during the translation of CPPs across various membranes. The proposed study encompassed the following specific aims: a) Identification of antimicrobial peptides that possess cell penetrating properties b) explore relationship between sequence composition and cell penetrating ability c) Role of secondary structure in determining cell penetrating ability d) Effect of membrane composition on cell penetrating ability of peptides. The study will be executed as two projects, project-1 will address specific aims a-c and project-2 will address specific aim-d. This study will lead to the understanding of the structure-activity relationships of CPPs when traversing across lipid bilayers.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此，可以在其他清晰的条目中表示。列出的机构是 对于中心，这不一定是调查员的机构。 药物设计和高通量筛查技术的进步导致了许多靶向各种细胞内分子的疗法和诊断剂的设计。但是，这些药物和诊断剂的生物传递是其正确靶标仍然是一个重大挑战。在所有早期铅分子中，近30％的铅分子与维特罗测试确定的靶标具有很高的亲和力，因为它们无法达到其预期靶标，因此无法进入临床步道（Lipinski，2001）。同样，将亲水性分子跨过血脑屏障仍然是一个同样具有挑战性的问题。因此，越来越多的努力来开发可以通过生物膜的新型分子，并可以用作有效递送药物的车辆。在过去的十年中，已经鉴定出了几个能够在细胞内递送药物的细胞穿透肽（CPP）。这些肽可以源自蛋白质，被称为蛋白质转导域，已知可以有效地横向生物膜。尽管实际的作用机理尚不清楚，但众所周知，该过程是受体和转运蛋白独立的（Derossi等，1996）。易位也不是介导的内吞作用，可以直接靶向脂质双层（Frankel等，1988和Plank等，1998）。因此，需要建立易位肽与脂质双层之间的直接接触。实验观察结果指出，在肽转运过程中，肽会导致毛孔形成，融合以及暂时的不稳定引起的膜重组（Mangoni等，1996）。本项目将重点关注CPP在各种膜上翻译过程中所涉及的结构机制。拟议的研究涵盖了以下特定目的：a）鉴定具有细胞穿透性特性的抗菌肽b）探索序列组成与细胞穿透能力之间的关系c）二级结构在确定细胞渗透能力d）膜组成对细胞渗透能力中的作用d）肽的穿透能力。该研究将作为两个项目执行，项目1将解决特定的目标A-C，而项目2将解决特定的AIM-D。这项研究将导致对CPP的结构活性关系的理解。