Combinatorial Peptidomimetics as Antineoplastics

作为抗肿瘤药的组合肽模拟物

• 批准号: 6465958
• 负责人: TODD D GIORGIO
• 金额: $ 16.74万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-06-01 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6465958
• 关键词: antineoplastics; bacterial virus; bioengineering /biomedical engineering; biomimetics; cancer prevention; chemical stability; chemical structure function; combinatorial chemistry; drug delivery systems; drug discovery /isolation; flow cytometry; gene expression; high throughput technology; ligands; microcapsule; neoplasm /cancer chemotherapy; peptide analog; peptide chemical synthesis; peptide library; protein sequence; receptor binding; stereoisomer; transfection /expression vector

DESCRIPTION (provided by applicant): We propose to unlock the pharmaceutical potential of cancer targeting peptide ligands identified by phage display. The use of peptides as drugs or delivery adjuvants is limited by their reaction to in vivo conditions. This work brings together expertise in four different fields of science and medicine to develop novel tools and methods for the creation and screening of peptidomimetic targeting molecules suitable for in vivo use. The combination of material science particle technology, peptidomimetic combinatorial chemistry, flow cytometry-based biological testing and clinical medicine promises to yield a general, powerful and scalable screening method for targeting molecules of practical value in the treatment of human disease. The integrated, multidisciplinary and multi institutional solution proposed here is essential to reorganize the gateway to drug discovery based on peptide sequences. This application compliments and extends the existing technology of biopanning phage display for the identification of cancer targeting ligands. We propose to start with peptide sequences identified by other research laboratories as ligands to specific target structures such as tumor endothelium. A peptidomimetic combinatorial library will be prepared based on these, targeting peptide structures. The combinatorial library will contain structures that are unavailable in phage display such as d- amino acids and non-peptide molecules. This approach marries the best characteristics of phage display and traditional pharmaceutical discovery to efficiently create molecules that have both target affinity and in vivo stability. Each member of this combinatorial library will be synthesized on a microsphere with unique properties that allow sorting by flow cytometry. Peptides cleaved from microspheres screened by flow cytometry on the basis of ligand-target recognition will be characterized and synthesized in quantity. These candidate ligands will undergo quantitative biological evaluation of binding strength, binding specificity and stability under simulated in vivo conditions. Stability and probable suitability for in vivo application as targeting adjuvants for pharmacological and radiological interventions or for gene therapies, is overseen in this work by a radiation oncologist with current clinical practice and an active, related research program. The studies described here will demonstrate the proof-of-concept using fundamental scientific principles and will produce examples of peptidomimetic targeting ligands. The products of this work will become preliminary data leading to the discovery and validation of molecular ligands for cancer prevention or treatment intervention consistent with the goal of this PA.

描述(由申请人提供)： 我们建议释放肿瘤靶向多肽的药用潜力 通过噬菌体展示鉴定配基。多肽作为药物或载体的使用 佐剂受限于它们对体内条件的反应。这部作品 汇集了科学和医学四个不同领域的专业知识 开发新的工具和方法来创建和筛选 适合体内使用的多肽类靶向分子。 材料科学与粒子技术、多肽技术的结合 基于组合化学、流式细胞术的生物检测与临床 医学有望产生一种通用的、强大的和可扩展的筛查方法 用于靶向在治疗人类疾病中具有实用价值的分子。 建议的综合、多学科和多机构解决方案 这是重组基于多肽的药物发现门户的关键 序列。 这项应用是对现有生物扫描技术的补充和扩展 噬菌体展示用于肿瘤靶向配体的识别。我们建议 从其他研究实验室确定的多肽序列开始 与特定靶结构(如肿瘤内皮)的配体。一个 在此基础上拟合成多肽组合文库， 靶向多肽结构。组合库将包含 在噬菌体展示中不可用的结构，如d-氨基酸和 非肽分子。这种方法结合了 噬菌体展示和传统药物发现高效创建 既有靶向亲和力又有体内稳定性的分子。每名成员 的组合文库将在微球上进行合成 允许通过流式细胞仪进行分类的特性。从以下来源裂解的肽 基于配体-靶点的流式细胞术筛选微球 识别将在数量上进行表征和合成。这些候选人 配体将接受结合强度的定量生物学评估， 在模拟体内条件下的结合特异性和稳定性。 作为靶向的体内应用的稳定性和可能性 用于药物和放射干预或用于基因的佐剂 治疗，在这项工作中由当前的放射肿瘤学家监督 临床实践和积极的相关研究计划。这些研究 此处描述的将使用基础知识来演示概念验证 科学原理，并将产生模拟多肽靶向的例子 配基。这项工作的产品将成为初步数据，导致 癌症预防或治疗分子配体的发现和验证 治疗干预符合本PA的目标。