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; 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）： 我们建议解锁靶向肽的癌症的药物潜力 通过噬菌体显示标识的配体。 使用肽作为药物或输送 佐剂受到对体内条件的反应的限制。 这项工作 将科学和医学领域的四个不同领域的专业知识汇集到 开发新颖的工具和方法来创建和筛选 适合体内使用的肽类拟合靶向分子。 材料科学粒子技术，肽类似的组合 组合化学，基于流式细胞术的生物学测试和临床 医学有望产生一般，强大且可扩展的筛查方法 用于针对治疗人类疾病的实用价值的分子。 提出的综合，多学科和多机构解决方案 这对于重组基于肽的药物发现的门户至关重要 序列。 此应用程序称赞并扩展了现有的生物封装技术 噬菌体显示，用于鉴定靶向配体的癌症。 我们建议 首先从其他研究实验室确定的肽序列开始 特定靶结构（例如肿瘤内皮）的配体。 一个 肽合组合库将根据这些图书馆准备 靶向肽结构。组合库将包含 在噬菌体显示中不可用的结构，例如D-氨基酸和 非肽分子。 这种方法嫁给了最佳特征 噬菌体显示和传统的药物发现有效地创建 具有目标亲和力和体内稳定性的分子。 每个成员 该组合库中的库将在以独特的微球上合成 允许通过流式细胞仪进行排序的属性。 肽从裂痕 根据配体目标，通过流式细胞仪筛选的微球 识别将以数量的特征和合成。这些候选人 配体将对结合强度进行定量生物学评估， 在模拟的体内条件下的结合特异性和稳定性。 稳定性和可能适合在体内应用作为靶向的适用性 药理和放射学干预措施或基因的辅助药 疗法是由一名辐射肿瘤学家监督的 临床实践和积极的相关研究计划。 研究 此处描述的将证明使用基本的概念证明 科学原理，将产生肽型靶向的例子 配体。 这项工作的产品将成为初步数据 发现和验证分子配体用于预防癌症或 治疗干预与此PA的目标一致。