Oral delivery of 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-小分子治疗剂的发现和开发的挑战性目标。使用肽来调节细胞内过程的概念已经研究了几十年，因为肽在体内的每个细胞中都起着核心作用。然而，肽具有严重的缺点。它们缺乏口服生物利用度，它们相对不能穿过细胞膜，这限制了它们的细胞外干预，并且它们难以制造。克服这些障碍的一种新方法是使用胱氨酸结微蛋白（CKM）技术作为载体来递送生物活性肽。CKM具有独特和有益的药物样性质，可能解决以前困扰肽类药物的关键问题。由于它们的小尺寸，CKM被认为相对良好地渗透通过肠粘膜。它们可以通过化学合成或重组技术相对便宜地大规模生产。一些CKM已经证明了进入细胞的能力。CKM是可合成优化的，并且具有潜在的口服生物利用度。重要的是，它是可行的，以纳入药理信息的氨基酸序列的CKM显示所需的功能，如高酶的稳定性和良好的渗透行为。因此，使用CKMs作为药物载体口服递送靶向细胞内蛋白质-蛋白质相互作用的肽可能成为一种有前途的新方法。我们提出了研究来评估这种方法在完善的模型系统中肽递送的适用性，使用NBD肽选择性地靶向NF-B信号转导途径的炎症活性。 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我们治疗疾病的能力之间存在巨大差距。用生物活性肽调节“不可用药的”细胞内过程的策略历来失败，因为大多数肽固有地不稳定并且缺乏膜渗透性。胱氨酸结微蛋白（CKM）具有独特的药物样性质，可能解决以前困扰肽类药物的关键问题。我们建议评估CKM技术作为口服给药靶向细胞内蛋白质-蛋白质相互作用的生物活性肽的分子药物递送载体的适用性。

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.