STRUCTURE BASED DESIGNS OF CELL PENETRATING PEPTIDES

基于结构的细胞穿透肽设计

• 批准号: 7956251
• 负责人: Sandhya Kortagere
• 金额: $ 0.08万
• 依托单位: CARNEGIE-MELLON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7956251
• 关键词: Address; Affinity; Biological; Biomedical Research; Blood - brain barrier anatomy; Cells; Clinical; Computer Retrieval of Information on Scientific Projects Database; Diagnostic; Drug Delivery Systems; Drug Design; Endocytosis; Funding; Grant; High Performance Computing; Institution; Lead; Lipid Bilayers; Mediating; Membrane; Peptides; Pharmaceutical Preparations; Process; Property; Proteins; Research; Research Personnel; Resources; Role; Source; Staging; Structure; Structure-Activity Relationship; Technology; Therapeutic; Translations; United States National Institutes of Health; antimicrobial peptide; base; design; high throughput screening; in vitro testing; 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 (Temsamani et al., 2004). 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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 药物设计和高通量筛选技术的进步导致了许多针对各种细胞内分子的治疗剂和诊断剂的设计。然而，将这些药物和诊断剂生物递送至正确的靶点仍然是一个重大挑战。近 30% 的早期先导分子与体外测试确定的靶点具有高亲和力，但由于无法达到预期靶点而未能进入临床试验（Lipinski，2001）。同样，跨血脑屏障运输亲水分子仍然是一个同样具有挑战性的问题。因此，人们越来越努力地开发能够穿过生物膜并可用作有效药物递送载体的新型分子（Temsamani 等，2004）。在过去的十年中，已经鉴定出几种能够在细胞内输送药物的细胞穿透肽（CPP）。这些肽可以衍生自蛋白质，被称为蛋白质转导域，已知它们可以有效地穿过生物膜。尽管实际的作用机制尚不清楚，但人们普遍认为该过程不依赖于受体和转运蛋白（Derossi et al., 1996）。该易位也不是内吞作用介导的，并且可以直接靶向脂质双层（Frankel等人，1988和Plank等人，1998）。因此，需要在易位肽和脂质双层之间建立直接接触。实验观察发现，在肽易位过程中，肽会由于孔的形成、融合以及暂时的不稳定而诱导膜重组（Mangoni 等人，1996）。本项目将重点研究 CPP 跨各种膜翻译过程中涉及的结构机制。拟议的研究涵盖以下具体目标：a）鉴定具有细胞穿透特性的抗菌肽b）探索序列组成与细胞穿透能力之间的关系c）二级结构在决定细胞穿透能力中的作用d）膜组成对肽细胞穿透能力的影响。该研究将作为两个项目执行，项目 1 将解决具体目标 a-c，项目 2 将解决具体目标 d。这项研究将有助于理解 CPP 穿越脂质双层时的结构-活性关系。