Using Dendrimers to Design Multivalent Therapeutic Agents

使用树枝状聚合物设计多价治疗剂

• 批准号: 8236550
• 负责人: Mary J Cloninger
• 金额: $ 30.21万
• 依托单位: MONTANA STATE UNIVERSITY - BOZEMAN
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8236550
• 关键词: Acetylgalactosamine; Acquired Immunodeficiency Syndrome; Adhesions; Affinity; Alzheimer' s Disease; Animal Model; Antigens; Arbitration; Architecture; Avidity; Binding; Biological; Biological Assay; Biological Models; Biological Process; Biology; Caenorhabditis elegans; Carbohydrates; Cell Adhesion; Cell physiology; Cells; Chemotaxis; Collaborations; Dendrimers; Development; Diabetes Mellitus; Disease; Environment; Enzyme-Linked Immunosorbent Assay; Event; Exhibits; Exposure to; Fluorescence; Fluorescence Anisotropy; Funding; Galactose; Galactose Binding Lectin; Galectin 1; Galectin 3; Generations; Goals; Individual; Influenza; Institutes; Kinetics; Lactose; Ligands; Malignant Neoplasms; Mediating; Mediator of activation protein; Metalloproteases; Migration Assay; Molecular Sieve Chromatography; N-acetyllactosamine; Neoplasm Metastasis; Pathway interactions; Pattern; Peptides; Play; Process; Prodrugs; Property; Proteins; Relative (related person); Research; Role; Structure; Surface Plasmon Resonance; System; Techniques; Testing; Therapeutic; Therapeutic Agents; Thompson-Friedenreich Antigen; Toxic effect; Universities; angiogenesis; base; cancer cell; carbohydrate binding protein; design; extracellular; in vivo; light scattering; molecular recognition; mouse model; novel; programs; receptor; research study; small molecule; tool

DESCRIPTION (provided by applicant): The overarching goal of this research program is to develop synthetic multivalent frameworks for the discernment and manipulation of biological recognition processes that are important in intercellular interactions. Multivalency plays a critical role in many biological interactions, and the development of synthetic multivalent systems to systematically probe these processes is critical for advancement of the rational development of multivalent therapeutics. Because typical individual receptor/ligand interactions in biology are often weak, augmentation of these interactions using multivalency can enhance functional avidity. Moreover, multivalent interactions can create patterns of ligands that can be used to modulate processes in novel ways, and these architectures of structure cannot be formed by traditional small-molecule therapeutics. The proposed research describes the development of dendrimers as tools to advance the understanding of the requirements for multivalent frameworks that are designed to mediate multivalent cancer cellular recognition processes. Our hypothesis is that carbohydrate functionalized dendrimers can be used to form clusters of galectins and that these galectin/glycodendrimer clusters will effectively arbitrate the intercellular recognition events of cancer cells. We have chosen glycodendrimers as the multivalent frameworks for the proposed studies because of the ease of manipulation of their size (generation) and of their end group functionalization. We have chosen galectins as our target proteins because of their known functions in cancer processes. The three specific aims are as follows. 1) Synthesize new carbohydrate-functionalized dendrimers. 2) Characterize the glycodendrimer/galectin binding interactions. 3) Perform cell based and animal model (C. elegans) assays with glycodendrimers. For specific aim 1, chemoenzymatic syntheses to form N-acetyllactosamine and Thomsen-Friedenriech antigen functionalized dendrimers are proposed. The synthesis of dendrimers bearing peptide substrates for matrix metalloproteases is also proposed. For specific aim 2, characterization of glycodendrimer/galectin aggregates is proposed using fluorescence lifetime waveform, fluorescence anisotropy, size exclusion chromatography-multiangle light scattering, surface plasmon resonance and ELISA experiments. Because of the effect of galectins -1 and -3 on cancer cellular aggregation processes, our goal is to characterize the binding affinity of the glycodendrimer/galectin interactions and the pattern of galectin that is displayed to the cells in the presence of glycodendrimers. For specific aim 3, we will perform angiogenesis and cellular adhesion assays in collaboration with Dr. Avraham Raz of the Karmanos Cancer Institute at Wayne State University. We also propose to perform homotypic cellular aggregation assays, chemotaxis and migration assays, mechanoelastic studies, kinetic studies on release of prodrug mimics, and studies with C. elegans. PUBLIC HEALTH RELEVANCE: Multivalent interactions, which occur when two or more molecular recognition events take place simultaneously between two partners, play a critical role in many biological processes. Diseases with multivalent aspects include AIDS, influenza, Alzheimer's disease, diabetes, and cancer. The proposed research describes the development of glycodendrimers as tools to advance the understanding of the requirements for multivalent frameworks that are designed to mediate multivalent cancer cellular recognition processes. The hypothesis that will be tested in the proposed research is that glycodendrimers will form clusters of galectins (carbohydrate binding proteins) and that these galectin/glycodendrimer clusters will effectively arbitrate intercellular recognition events.

描述（由申请人提供）：该研究计划的总体目标是开发合成的多价框架，以辨别和操纵在细胞间相互作用中很重要的生物识别过程。多价性在许多生物学相互作用中起着至关重要的作用，并且合成多价系统系统地探测这些过程对于发展多价疗法的合理发展至关重要。由于生物学中典型的单个受体/配体相互作用通常很弱，因此使用多价性能增强这些相互作用可以增强功能性感。此外，多价相互作用可以创建配体模式，这些模式可用于以新颖的方式调节过程，并且这些结构架构不能由传统的小分子疗法形成。 拟议的研究将树枝状聚合物的发展描述为促进对旨在介导多价癌症细胞识别过程的多价框架要求的理解的工具。我们的假设是，碳水化合物官能化的树突聚合物可用于形成半乳糖蛋白簇，并且这些甲状腺蛋白/糖胶中二聚体簇将有效地仲裁癌细胞的细胞间识别事件。我们选择了糖结基因七聚体作为拟议研究的多价框架，因为它们的大小（生成）及其最终组功能化的操纵易于操纵。由于它们在癌症过程中具有已知功能，因此我们选择了甲状腺蛋白作为靶蛋白。 三个具体目标如下。 1）合成新的碳水化合物官能化的树枝状聚合物。 2）表征糖胶中/半乳糖素结合相互作用。 3）用糖结二聚体进行基于细胞和动物模型（秀丽隐杆线虫）测定。 对于特定的目标1，提出了形成N-乙酰乳糖苷和Thomsen-Friedenriech抗原功能化树状聚合物的化学酶合成。还提出了带有肽底物的基质基质金属蛋白酶的树状聚合物的合成。对于特定目标2，建议使用荧光寿命波形，荧光各向异性，尺寸排除色谱 - 形式 - 甲状化光散射，表面等离子体共振和ELISA实验提出糖结聚合物/半凝集素聚集体的表征。由于甲状腺蛋白-1和-3对癌细胞聚集过程的影响，我们的目标是表征糖结二烯二聚体/乳糖素相互作用的结合亲和力以及在糖结二聚体存在下显示给细胞的lectectin模式。对于特定的目标3，我们将与韦恩州立大学Karmanos癌症研究所的Avraham Raz博士合作进行血管生成和细胞粘附测定。我们还建议进行同型细胞聚集测定，趋化性和迁移测定，机械弹性研究，有关前药模仿的释放的动力学研究以及与秀丽隐杆线虫的研究。 公共卫生相关性：多价相互作用，这是在两个伴侣之间同时发生两个或多个分子识别事件时发生的，在许多生物过程中起着至关重要的作用。具有多价方面的疾病包括艾滋病，流感，阿尔茨海默氏病，糖尿病和癌症。拟议的研究描述了糖结基因聚合物的开发是促进对旨在介导多价癌细胞识别过程的多价框架要求的理解的工具。在拟议的研究中将检验的假设是，糖结基因聚合物将形成半乳肠蛋白（碳水化合物结合蛋白），并且这些甘蓝蛋白/糖结二聚体二聚体簇将有效地仲裁仲裁的细胞间识别事件。