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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 药物设计和高通量筛选技术的进步已经导致设计了许多靶向各种细胞内分子的治疗剂和诊断剂。然而，将这些药物和诊断剂生物递送到其正确的靶标仍然是一个重大挑战。通过体外试验确定的对靶点具有高亲和力的所有早期先导分子中，近30%由于无法达到其预期靶点而无法进入临床试验（Lipinski，2001）。类似地，运输亲水性分子穿过血脑屏障仍然是同样具有挑战性的问题。因此，有越来越多的努力来开发新的分子，可以通过生物膜，并可以用作车辆有效的药物输送。在过去的十年中，已经鉴定了几种能够在细胞内递送药物的细胞穿透肽（CPP）。这些肽可以衍生自蛋白质，并且被称为蛋白质转导结构域，已知其有效地穿过生物膜。尽管实际的作用机制尚不清楚，但广泛理解的是，该过程是不依赖于受体和转运蛋白的（Derossi等人，1996年）的报告。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年）。因此，需要在易位肽和脂质双层之间建立直接接触。实验观察已经注意到，在肽易位过程中，由于孔形成、融合以及暂时的去稳定化，肽诱导膜重组（Mangoni等人，1996年）。本项目将集中在跨各种膜的CPP翻译过程中所涉及的结构机制。拟进行的研究包括以下具体目的：a）鉴定具有细胞穿透性质的抗菌肽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）膜组成对肽的细胞穿透能力的影响。本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a-d。这项研究将导致跨脂质双层时的结构与活性关系的CPP的理解。