Combinatorial Peptidomimetics as Antineoplastics

作为抗肿瘤药的组合肽模拟物

• 批准号: 6623455
• 负责人: TODD D GIORGIO
• 金额: $ 16.73万
• 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 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623455
• 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）： 我们建议释放癌症靶向肽的药学潜力 通过噬菌体展示鉴定配体。 肽作为药物或递送的用途 佐剂受其对体内条件的反应限制。 这项工作 汇集了四个不同科学和医学领域的专业知识， 开发新的工具和方法，用于创建和筛选 适合于体内使用的肽模拟物靶向分子。 结合材料科学、粒子技术、拟肽 组合化学、基于流式细胞术的生物检测和临床 医学有望产生一种通用的、强大的和可扩展的筛选方法 用于靶向在人类疾病治疗中具有实用价值的分子。 提出的综合、多学科和多机构解决方案 因此，有必要重新组织基于肽的药物发现的途径 序列的 该应用补充和扩展了现有的生物淘选技术 噬菌体展示用于鉴定癌症靶向配体。 我们提出 从其他研究实验室鉴定的肽序列开始， 特异性靶结构如肿瘤内皮的配体。 一 拟肽组合文库将在此基础上制备， 靶向肽结构。组合文库将包含 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 噬菌体展示和传统的药物发现， 具有靶向亲和力和体内稳定性的分子。 每个成员 将在微球上合成， 允许通过流式细胞术进行分选的性质。 肽从 基于配体靶向的流式细胞术筛选微球 识别将在数量上被表征和合成。这些候选 配体将进行结合强度的定量生物学评价， 在模拟体内条件下的结合特异性和稳定性。 稳定性和作为靶向的体内应用的可能适用性 用于药理学和放射性干预或基因治疗的佐剂 在这项工作中，由放射肿瘤学家监督， 临床实践和积极的相关研究计划。 研究 这里描述的将使用基本的 科学原理，并将产生肽模拟靶向的例子 配体。 这项工作的成果将成为初步数据， 用于癌症预防的分子配体的发现和验证， 治疗干预与本PA的目标一致。

项目成果

Quantitative measurement of multifunctional quantum dot binding to cellular targets using flow cytometry.

使用流式细胞术对多功能量子点结合的多功能量子点结合。

• DOI: 10.1002/cyto.a.20677
• 发表时间: 2009-05
• 期刊: Cytometry. Part A : the journal of the International Society for Analytical Cytology
• 作者: Smith RA;Giorgio TD
• 通讯作者: Giorgio TD