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Synthesis of Various C-Linked Glycopeptides of Biomedical Interest

各种具有生物医学意义的 C-连接糖肽的合成

基本信息

批准号：
7363833
负责人：
Ernest G Nolen
金额：
$ 20.68万
依托单位：
COLGATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7363833
关键词：
Acetamides Amino Acids Antibodies Antibody Formation Antigens Antineoplastic Agents Architecture Attention Autoantibodies Biological Biological Assay Biological Markers Bladder Bladder Neoplasm Cancer Diagnostics Cancer Patient Carbohydrates Carbon Cell surface Cells Chemistry Class Collaborations Computer-Assisted Image Analysis Development Diagnostic Disease Early Diagnosis Enzyme-Linked Immunosorbent Assay Enzymes Epithelial Cells Glycine Glycopeptides Glycosides Goals Growth Factor Homoserine Human Immune response Immunotherapy Interstitial Cystitis Lead Length Link MUC4 mucin Membrane Methodology Methods Modeling Modification Mucin-1 Staining Method Mucins National Cancer Institute Neoplasm Metastasis Patients Pattern Peptide Conformation Peptides Preparation Process Reaction Research Route Science Serum Staging Structure Tandem Repeat Sequences Testing Therapeutic Tn antigen Tumor Cell Line Variant analog base cancer therapy cell growth chemical synthesis desire glycosylation glycosyltransferase inhibitor/antagonist inorganic phosphate insight interest molecular dynamics molecular modeling neoplastic cell neutralizing antibody pancreatic neoplasm phosphonate protein aminoacid sequence receptor binding sugar tumor tumor growth vaccine development

项目摘要

DESCRIPTION (provided by applicant): Chemical synthesis will provide homogeneous and robust molecules that mimic the O-glycopeptide architecture of O-mucins, which are associated with tumor cells of mucosal membranes. Particular attention is given to developing versatile and expedient methods to prepare these glycopeptide mimics. The prepared materials will be used to better define the structural parameters by which these molecules interact and function, and to develop potential therapeutics or diagnostics for cancer. The glyco-domains displayed on the cell surface act as key immunological recognition features directly or indirectly involved in antibody-antigen interactions. Many tumor cells have truncated glycosylation patterns that are antigenic, giving rise to their study as biomarkers for disease and to their potential for raising a neutralizing antibody response for vaccine development. The O-mucins maintain a common core saccharide, O-GalNAc 1-linked to Ser/Thr, known as Tn antigen. The proposed research is divided into four aims. Aim 1 entails the development of expedient synthetic routes to the C-linked mimics of Tn antigen, specifically - Ser, Thr, Ala, Hse variations. Syntheses entail metathesis reactions between sugar-derived 1-heptenes and alkenyl substituted glycine derivatives. The inclusion of aim 2 will test the versatility of the synthetic method from aim 1 toward compounds with inhibitory activities for glyco-processing enzymes. Employing a common synthetic intermediate, the efficient preparation of iminosugars and glycosyl phosphate mimics will be ascertained. The products from aim 1 will be incorporated into glycopeptide sequences in aim 3. First, a model nonapeptide will be prepared for exploration of fundamental conformational influences. Next, C-glycopeptide synthesis will target three biomedically significant peptides: a tandem repeat of MUC4 (expressed in human pancreatic tumor cells), a tandem repeat of MUC1 (over-expressed with truncated glycoforms in numerous tumor cells), and the antiproliferative factor (APF) glycopeptide that inhibits epithelial cell growth in the bladder. Aim 4, conducted in collaboration with Dr. J. J. Barchi at the National Cancer Institute (NCI)-Frederick, will examine the effects of glycopeptide conformational changes potentiated by C-versus O-linkages, and by variation of carbon chain length. These modifications will have implications for receptor binding and will impact biological activity. Immunological and other biomedical attributes of the C-linked mucins and APF will be investigated by Barchi and supporting labs at NCI-Frederick. Chemical synthesis will provide homogeneous and robust molecules that mimic the glycopeptide architecture associated with tumor cells of mucosal membranes. Particular attention is given to developing versatile and expedient methods to prepare these glycopeptide mimics. The prepared materials will be used to better define the structural parameters by which these molecules interact and function, and to develop potential therapeutics or diagnostics for cancer.

描述（由申请人提供）：化学合成将提供模拟O-粘蛋白的O-糖肽结构的均质和稳健的分子，O-粘蛋白与粘膜的肿瘤细胞相关。特别注意开发通用和方便的方法来制备这些糖肽模拟物。准备的材料将用于更好地定义这些分子相互作用和发挥作用的结构参数，并开发潜在的癌症治疗或诊断方法。在细胞表面上展示的糖结构域充当直接或间接参与抗体-抗原相互作用的关键免疫识别特征。许多肿瘤细胞具有截短的糖基化模式，这些糖基化模式是抗原性的，这引起了它们作为疾病生物标志物的研究以及它们提高疫苗开发的中和抗体应答的潜力。0-粘蛋白保持共同的核心糖，O-GalNAc 1-连接到Ser/Thr，称为Tn抗原。拟议的研究分为四个目标。目的1需要开发Tn抗原的C-连接模拟物，特别是- Ser，Thr，Ala，Hse变体的有利合成路线。合成需要糖衍生的1-庚烯和烯基取代的甘氨酸衍生物之间的复分解反应。目标2的纳入将测试目标1的合成方法对具有糖加工酶抑制活性的化合物的通用性。采用一个共同的合成中间体，有效地制备亚氨基糖和糖基磷酸酯模拟物将被确定。目标1的产物将被整合到目标3的糖肽序列中。首先，将制备模型九肽用于探索基本构象影响。接下来，C-糖肽合成将靶向三种具有生物医学意义的肽：MUC 4的串联重复序列（在人胰腺肿瘤细胞中表达）、MUC 1的串联重复序列（在许多肿瘤细胞中与截短的糖型过表达）和抑制膀胱上皮细胞生长的抗增殖因子（APF）糖肽。目标4，与J. J. Barchi博士合作进行，美国国家癌症研究所（NCI）-弗雷德里克，将研究的影响，糖肽构象变化增强的C-与O-连接，并通过碳链长度的变化。这些修饰将对受体结合产生影响，并将影响生物活性。C-连接粘蛋白和APF的免疫学和其他生物医学属性将由Barchi和NCI-Frederick的支持实验室进行研究。化学合成将提供模拟与粘膜肿瘤细胞相关的糖肽结构的均质和稳健的分子。特别注意开发通用和方便的方法来制备这些糖肽模拟物。所制备的材料将用于更好地定义这些分子相互作用和功能的结构参数，并开发潜在的癌症治疗或诊断方法。