Synthetic Probes of Protein Prenylation

蛋白质异戊二烯化的合成探针

• 批准号: 8070533
• 负责人: H Peter Spielmann
• 金额: $ 30.51万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070533
• 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; farnesyl pyrophosphate; geranylgeranyl diphosphate; in vivo; inhibitor/antagonist; innovation; isoprenoid; lipophilicity; novel; prenyl; prenylation; programs; protein farnesyltransferase; protein function; protein geranylgeranyltransferase; public health relevance; tool; tumor progression

DESCRIPTION (provided by applicant): 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 substrate 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. PUBLIC HEALTH RELEVANCE 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.

描述（由申请人提供）：类异戊二烯脂质的共价修饰（异戊二烯化）对于许多参与细胞信号传导和癌症的蛋白质来说是一个关键的翻译后事件。该研究计划的主要目标是设计和测试异戊二烯基功能抑制剂，并鉴定和表征体内法呢基化的蛋白质。该提案中概述的研究将导致制备新工具来探测异戊二烯基转移酶蛋白法呢基转移酶（FTase）和蛋白香叶基香叶基转移酶（GGTase-I）的特异性，从而进一步开发异戊烯基功能抑制剂，并确定新的异戊二烯化蛋白作为治疗干预的潜在靶点。通过改变异戊二烯脂质的化学结构，我们正在开发试剂来探测翻译后修饰的生物学功能。利用异戊二烯基团形成异戊二烯基转移酶中肽底物结合位点的重要部分这一事实，使我们能够开发异戊二烯基功能的肽选择性抑制剂。这些非天然类似物可以选择性干扰特定的异戊二烯化靶标，并可以提供先导化合物来减轻与完全抑制蛋白质异戊二烯化相关的潜在毒性。特别是，非天然类似物可能有助于更全面地了解替代异戊二烯化在 K-Ras 等癌基因逃避法呢基转移酶抑制剂 (FTI) 中所起的作用。了解现有和未来 FTI 和香叶基香叶基转移酶抑制剂 (GGTI) 的临床效果的关键是鉴定 FTase 和 GGTase-I 的体内底物。我们的创新策略是使用非天然、可转移的异戊二烯类似物和类似物特异性单克隆抗体来鉴定异戊二烯化细胞蛋白，这将为异戊二烯化抑制剂的细胞靶点提供有价值的信息。我们期望这些研究能够鉴定出以前未知的异戊二烯化蛋白质。该项目的具体目标是：1）合成法尼基和香叶基香叶基二磷酸类似物以研究蛋白质异戊二烯化。 2) 筛选这些化合物的 FTase 和 GGTase-I 底物特异性并开发异戊烯基功能抑制剂。 3) 细胞中异戊二烯化蛋白的鉴定。这些研究的结果可能为治疗癌症的新分子提供线索，并确定开发抗癌疗法的新分子靶点。 公共卫生相关性 大量证据表明，通常由异戊二烯基修饰的蛋白质在癌症进展中发挥着核心作用。我们建议设计和测试异戊二烯基功能抑制剂，并鉴定和表征用异戊二烯基团修饰的蛋白质。这些研究的结果可能会为治疗癌症的新分子提供线索，并确定新的分子靶点以开发未来的抗癌疗法。

项目成果

Assessing the efficacy of protein farnesyltransferase inhibitors in mouse models of progeria.

• DOI: 10.1194/jlr.m002808
• 发表时间: 2010-02
• 期刊: Journal of lipid research
• 影响因子: 6.5
• 作者: Yang SH;Chang SY;Andres DA;Spielmann HP;Young SG;Fong LG
• 通讯作者: Fong LG

LINCing lamin B2 to neuronal migration: growing evidence for cell-specific roles of B-type lamins.

• DOI: 10.4161/nucl.1.5.12830
• 发表时间: 2010-09
• 期刊: Nucleus (Austin, Tex.)
• 作者: Coffinier C;Fong LG;Young SG
• 通讯作者: Young SG

Anticancer activity of novel unnatural synthetic isoprenoids.

• 发表时间: 2010-07
• 期刊: Anticancer research
• 影响因子: 2
• 作者: V. Adams;D. DeRemer;Bojana Stevich;C. Mattingly;Becky Gallt;T. Subramanian;J. Troutman;H. Spielmann

Genetic studies on the functional relevance of the protein prenyltransferases in skin keratinocytes.

皮肤角质形成细胞中蛋白质异戊二烯基转移酶功能相关性的遗传学研究。

• DOI: 10.1093/hmg/ddq036
• 发表时间: 2010
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Lee,Roger;Chang,SandyY;Trinh,Hung;Tu,Yiping;White,AndrewC;Davies,BrandonSJ;Bergo,MartinO;Fong,LorenG;Lowry,WilliamE;Young,StephenG
• 通讯作者: Young,StephenG

Activating the synthesis of progerin, the mutant prelamin A in Hutchinson-Gilford progeria syndrome, with antisense oligonucleotides.

• DOI: 10.1093/hmg/ddp184
• 发表时间: 2009-07-01
• 期刊: Human molecular genetics
• 影响因子: 3.5
• 作者: Fong LG;Vickers TA;Farber EA;Choi C;Yun UJ;Hu Y;Yang SH;Coffinier C;Lee R;Yin L;Davies BS;Andres DA;Spielmann HP;Bennett CF;Young SG
• 通讯作者: Young SG