Synthetic Probes of Protein Prenylation

蛋白质异戊二烯化的合成探针

• 批准号: 8052002
• 负责人: H Peter Spielmann
• 金额: $ 8.5万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-15 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8052002
• 关键词: Active Sites; Antibodies; Binding Sites; Biochemical; Biological; Biological Assay; Biological Process; Biology; Cells; Chemical Structure; Dependence; Development; Dimethylallyltranstransferase; Discrimination; Drug Design; Enzymes; Event; Exhibits; Farnesyl Transferase Inhibitor; Funding; Future; Goals; Growth; Immunoprecipitation; Lead; Lipids; Malignant Neoplasms; Methods; Modification; Molecular Target; Monoclonal Antibodies; Oncogenes; Pathway interactions; Peptides; Play; Post-Translational Protein Processing; Preparation; Process; Protein Isoprenylation; Proteins; Proteomics; Reagent; Research; Role; Screening procedure; Signal Transduction; Site-Directed Mutagenesis; Specificity; Substrate Specificity; Techniques; Testing; Therapeutic Intervention; Toxic effect; Transformed Cell Line; analog; cancer therapy; cellular targeting; chemical synthesis; clinical effect; cytotoxicity; design; enzyme substrate; geranylgeranyl diphosphate; in vivo; inhibitor/antagonist; innovation; isoprenoid; lipophilicity; novel; prenyl; prenylation; programs; protein farnesyltransferase; protein function; protein geranylgeranyltransferase; tool; tumor progression

Covalent modification by isoprenoid lipids (prenylation) is a critical post-translational event for many proteins involved in cellular signaling and cancer. The primary goal of this research program is to design and test prenyl function inhibitors and to identify and characterize proteins that are farnesylated in vivo. The studies outlined in this proposal will result in the preparation of new tools to probe the specificity of the prenyltransferases protein- farnesyltransferase (FTase) and protein-geranylgeranyltransferase (GGTase-I), enable further development of prenyl function inhibitors and identify new prenylated proteins as potential targets for therapeutic intervention. By varying the chemical structure of the prenyl lipid, we are developing reagents to probe the biological function of the posttranslational modification. Taking advantage of the fact that the prenyl group forms a substantial part of the peptide substrate binding site in the prenyltransferases has allowed us to develop peptide selective inhibitors of prenyl function. These unnatural analogues may allow for the selective interference with specific prenylation targets and may provide lead compounds to alleviate the potential toxicity associated with complete inhibition of protein prenylation. In particular, the unnatural analogues may be useful to obtain a more complete understanding of the role that alternative prenylation plays in Farnesyl transferase inhibitor (FTI) evasion by oncogenes such as K-Ras. Critical to understanding the clinical effects of existing and future FTIs and geranylgeranyl transferase inhibitors (GGTIs), is the identification of in vivo substrates of FTase and GGTase-I. Our innovative strategy of using unnatural, transferable prenyl analogues and analogue specific monoclonal antibodies to identify prenylated cellular proteins will provide valuable information on the cellular targets of inhibitors of prenylation. We expect these studies to result in the identification of previously unknown prenylated proteins. The specific aims of this project are: 1) Synthesis of farnesyl and geranylgeranyl diphosphate analogues to study protein prenylation. 2) Screening these compounds for ubstrate specificity of FTase and GGTase-I and development of prenyl function inhibitors. 3) Identification of prenylated proteins in cells. The results from these studies may provide leads to new molecules to treat cancer and also identify new molecular targets to develop anti-cancer therapies. Substantial evidence points to the central role of proteins normally modified by a prenyl group in cancer progression. We propose to design and test prenyl function inhibitors and to identify and characterize proteins that are modified with prenyl groups. The results from these studies may provide leads to new molecules to treat cancer and also identify new molecular targets to develop future anti-cancer therapies.

异戊二烯类脂的共价修饰(异戊二烯基化)是许多蛋白质翻译后的关键事件 与细胞信号和癌症有关。这项研究计划的主要目标是设计和测试戊烯丙烷 功能抑制剂，并鉴定和表征体内法尼化的蛋白质。中概述的研究 这项提议将导致准备新的工具来探索前烯基转移酶蛋白的特异性- 法尼基转移酶(FTase)和蛋白香叶基香叶基转移酶(GGTase-I)使 并确定新的前烯基化蛋白作为治疗干预的潜在靶点。 通过改变戊烯基脂的化学结构，我们正在开发试剂来探索生物 翻译后修饰的功能。利用戊烯基团形成一个 异丙苯基转移酶中的大部分肽底物结合部位使我们能够开发出 异丙烯基功能的多肽选择性抑制剂。这些不自然的类似物可能会允许选择性地 干扰特定的预烯基化靶标，并可能提供先导化合物以减轻潜在的毒性 与蛋白质预烯基化的完全抑制有关。特别是，非自然的类似物可能是有用的 为了更全面地了解交替的戊烯基化在法尼基转移酶中所起的作用 K-RAS等癌基因对抑制物(FTI)的逃逸。对了解现有药物的临床效果至关重要 以及未来的FTIs和香叶基转移酶抑制剂(GGTIs)，是体内底物的鉴定 FTase和GGTase-I。我们使用非天然、可转移的戊烯基类似物和类似物的创新战略 特异性的单抗鉴定细胞蛋白将提供有价值的信息。 苯丙基化抑制剂的细胞靶点。我们预计这些研究将导致确认以前的 未知的前烯基化蛋白质。本课题的具体目标是：1)合成法尼基和香叶基香叶基 研究蛋白质预烯基化的二磷酸类似物。2)筛选这些化合物的底物特异性 FTase和GGTase-I与戊烯功能抑制剂的开发。3)青枯菌中预烯基化蛋白的鉴定 细胞。这些研究的结果可能会为治疗癌症的新分子提供线索，也可能识别新的 开发抗癌疗法的分子靶点。大量证据表明，通常由异丙烯基修饰的蛋白质在癌症中起着中心作用。 进步。我们建议设计和测试戊烯功能抑制剂，并鉴定和表征蛋白质。 它们被戊烯基团修饰。这些研究的结果可能会提供新分子的线索 治疗癌症，并确定新的分子靶点，以开发未来的抗癌疗法。