Cyclic Cell-Penetrating Peptides

环状细胞穿透肽

基本信息

批准号：
8818038
负责人：
Dehua Pei
金额：
$ 29.11万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-22 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8818038
关键词：
Affinity Amino Acids Binding Biological Cancer Cell Growth Cancer cell line Cell Nucleus Cell membrane Cells Charge Cyclic Peptides Cytoplasm Development Endocytosis Endosomes Eukaryotic Cell Family Glutamine Health Heparin Binding Human In Vitro Inorganic Sulfates Investigation Laboratories Libraries Lipids Location Malignant Neoplasms Malignant neoplasm of lung Mammalian Cell Membrane Modeling Nucleic Acids Oncogene Proteins Oncogenes Peptide Library Peptides Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phospholipids Plasma Proteins Ras Inhibitor Reporting Small Interfering RNA Structure-Activity Relationship Surface Testing Therapeutic Therapeutic Agents Unspecified or Sulfate Ion Sulfates Variant Vesicle anticancer activity arginylarginine combinatorial design drug discovery effective therapy extracellular hydrophilicity improved in vivo inhibitor/antagonist insight nonaarginine pH gradient peptidomimetics protein aminoacid sequence ras Proteins research study screening small molecule unilamellar vesicle uptake

项目摘要

DESCRIPTION (provided by applicant): The ability to cross the cell membrane and gain access to the cell interior is a requirement for any therapeutic agent intended for an intracellula target. Proteins, peptides, and small interfering RNA (siRNA) represent some of the emerging/expanding classes of therapeutic agents. However, these biological molecules are generally membrane impermeable on their own and must be delivered to the proper intracellular locations. Cell-penetrating peptides (CPPs) are short peptides (usually <30 amino acids) that have the ability to penetrate the plasma membrane of eukaryotic cells without causing significant membrane damage. Many CPPs have been discovered and some have been used to deliver a wide variety of cargos into cells. A major limitation of previous CPPs is that they have poor overall delivery efficiency due to inefficient endosomal escape. A new family of cyclic CPPs, e.g., cyclo(F?RRRRQ) (where ? is 2-naphthylalanine), was recently discovered in this laboratory and found to escape from the endosome efficiently. The overall objective of this project is to elucidate the mechanisms of CPP uptake and endosomal escape and develop more potent CPPs as general transporters for intracellular delivery of biological active molecules. Specific Aim 1 is to synthesize and screen a focused cyclic peptide library to identify additional and potentially more active cyclic CPPs. Specific Aim 2 is to test the limits of what ca be delivered by the cyclic CPPs and determine the mechanism of CPP endosomal release as well as the factors that control the endosomal escape efficiency. Finally, Specific Aim 3 is to utilize the cyclic CPPs to design cell permeable inhibitors against intracellular proteins such as the oncoprotein Ras.

描述（由申请人提供）：穿过细胞膜并进入细胞内部的能力是任何针对细胞内靶标的治疗剂的要求。蛋白质、肽和小干扰 RNA (siRNA) 代表了一些新兴/扩展的治疗剂类别。然而，这些生物分子本身通常是膜不可渗透的，必须被递送到适当的细胞内位置。细胞穿透肽 (CPP) 是短肽（通常<30 个氨基酸），能够穿透真核细胞的质膜而不造成明显的膜损伤。许多 CPP 已被发现，其中一些已被用于将各种货物输送到细胞中。先前 CPP 的一个主要限制是，由于内体逃逸效率低下，它们的整体递送效率较差。该实验室最近发现了一个新的环状 CPP 家族，例如环（F？RRRRQ）（其中？是 2-萘丙氨酸），并且发现它可以有效地从内体中逃逸。该项目的总体目标是阐明 CPP 摄取和内体逃逸的机制，并开发更有效的 CPP 作为生物活性分子细胞内递送的通用转运蛋白。具体目标 1 是合成和筛选重点环肽库，以识别其他且可能更具活性的环 CPP。具体目标 2 是测试环状 CPP 的递送极限，并确定 CPP 内体释放的机制以及控制内体逃逸效率的因素。最后，具体目标 3 是利用环状 CPP 设计针对细胞内蛋白（例如癌蛋白 Ras）的细胞渗透性抑制剂。