Oral delivery of peptides targeting intracellular protein-protein interactions

口服递送针对细胞内蛋白质-蛋白质相互作用的肽

• 批准号: 8251999
• 负责人: Mark W Nowak
• 金额: $ 22.92万
• 依托单位: ENCODE BIO, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-07 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8251999
• 关键词: Amino Acid Sequence; Analgesics; Behavior; Binding; Bioavailable; Biological; Biological Assay; Biological Availability; Biological Models; Caco-2 Cells; Carrageenan; Cell Membrane Permeability; Cell membrane; Cell model; Cells; Cellular Assay; Characteristics; Clinical; Complex; Cystine; Development; Diagnostic; Disadvantaged; Disease; Drug Delivery Systems; Drug Kinetics; Edema; Engineering; Family; Goals; Image; In Vitro; Inflammation; Inflammatory; Intervention; Intestinal Absorption; Intestinal Mucosa; Intestines; Label; Marketing; Measures; Modality; Modeling; Molecular; Monitor; Oral; Oral Administration; Peptide Hydrolases; Peptides; Permeability; Pharmaceutical Preparations; Phase; Phosphotransferases; Plague; Plasma; Play; Process; Production; Property; Proteins; Rattus; Recombinants; Relative (related person); Reporting; Role; Serum; Signal Transduction Pathway; Solid; Technology; Tertiary Protein Structure; Therapeutic; Therapeutic Agents; Toxic effect; Trypsin Inhibitors; base; chemical synthesis; cytotoxicity; design; disulfide bond; efficacy testing; extracellular; improved; in vivo; member; novel; novel strategies; pre-clinical; protein protein interaction; scaffold; small molecule; tumor; uptake

DESCRIPTION (provided by applicant): Modulation of intracellular protein-protein interactions has been - and remains - a challenging goal for the discovery and development of small-molecule therapeutic agents. The concept of using peptides to modulate intracellular processes has been investigated for decades, as peptides play a central role in every cell in the body. Yet peptides suffer from severe disadvantages. They lack oral bioavailability, their relative inability to cross the cell membrane confines them to extracellular interventions and they are difficult to manufacture. A novel approach to overcome these barriers is to use cystine-knot microprotein (CKM) technology as a vehicle to deliver bioactive peptides. CKMs are endowed with unique and beneficial drug-like properties that could potentially solve critical problems previously plaguing the peptide class of drugs. Due to their small size, CKMs are believed to permeate relatively well through intestinal mucosa. They can be produced via chemical synthesis or recombinant technology relatively inexpensively and in large scale. Some CKMs have demonstrated the ability to enter cells. CKMs are synthetically optimizable and potentially orally bioavailable. Importantly, it is feasible to incorporate pharmacophoric information into the amino acid sequence of a CKM displaying desired features such as high enzymatic stability and good permeation behavior. Therefore, the use of CKMs as pharmacophoric carriers in oral delivery of peptides targeting intracellular protein-protein interactions can become a promising novel approach. We propose studies to assess the suitability of this approach to peptide delivery in well-established model system, using the NBD peptide to selectively target the inflammatory activity of the NF-B signal transduction pathway. PUBLIC HEALTH RELEVANCE: There is a dramatic gap between our understanding of diseases and our ability to treat them because of the limitations inherent in existing drug platforms. Strategies to modulate "undruggable" intracellular processes with bioactive peptides have historically failed because most peptides are inherently unstable and lack membrane permeability. Cystine-knot microproteins (CKMs) are endowed with unique drug-like properties that could potentially solve critical problems previously plaguing the peptide class of drugs. We propose to assess the suitability of the CKM technology as a molecular drug delivery vehicle for oral administration of bioactive peptides targeting intracellular protein-protein interactions.

描述（由申请人提供）：细胞内蛋白质 - 蛋白质相互作用的调节一直是 - 并且仍然是发现和开发小分子治疗剂的挑战性目标。数十年来，已经研究了使用肽调节细胞内过程的概念，因为肽在体内每个细胞中都起着核心作用。然而，肽遭受严重的缺点。他们缺乏口服生物利用度，其相对无法越过细胞膜使它们局限于细胞外干预措施，并且很难制造。克服这些障碍的一种新型方法是将胱氨酸结微蛋白（CKM）技术用作提供生物活性肽的载体。 CKM具有独特而有益的药物样特性，这些特性可能会解决以前困扰肽类药物类别的关键问题。由于其尺寸很小，CKM被认为通过肠粘膜渗透相对较好。它们可以通过化学合成或重组技术相对廉价和大规模生产。一些CKM已经证明了进入细胞的能力。 CKM在合成方面是可优化的，并且可能口服生物利用。重要的是，将药物浮雕信息纳入CKM的氨基酸序列是可行的，该氨基酸序列显示出所需的特征，例如高酶促稳定性和良好的渗透行为。因此，将CKMs用作药物载体在靶向细胞内蛋白质蛋白相互作用的肽的口服递送中可以成为一种有前途的新方法。我们建议使用NBD肽选择性地靶向NF-B信号转导途径的炎症活性，以评估这种方法在良好的模型系统中对肽递送的适用性。 公共卫生相关性：由于现有药物平台固有的局限性，我们对疾病的理解与治疗它们的能力之间存在巨大差距。使用生物活性肽调节“不良”细胞内过程的策略在历史上失败了，因为大多数肽本质上是不稳定的，并且缺乏膜渗透性。胱氨酸结微蛋白（CKM）具有独特的类似药物样特性，这些特性可能会解决以前困扰肽类药物类别的关键问题。我们建议评估CKM技术作为一种分子药物递送工具的适用性，用于口服靶向细胞内蛋白质相互作用的生物活性肽。