Synthetic Probes of Protein Prenylation

类异戊二烯脂质的共价修饰（异戊二烯化）是许多蛋白质的关键翻译后事件 参与细胞信号传导和癌症。这项研究计划的主要目标是设计和测试异戊二烯 功能抑制剂以及鉴定和表征体内法尼基化的蛋白质。概述的研究 该提议将导致制备新的工具来探测异戊烯基转移酶蛋白的特异性， 法尼基转移酶（FTase）和蛋白质-香叶基香叶基转移酶（GGT酶-I），使得能够进一步开发 异戊烯基功能抑制剂，并确定新的异戊烯化的蛋白质作为治疗干预的潜在目标。 通过改变异戊烯基脂质的化学结构，我们正在开发试剂来探测生物学特性。 翻译后修饰的功能。利用异戊二烯基形成一个 异戊二烯基转移酶中的肽底物结合位点的相当大的一部分使我们能够开发 异戊二烯基功能的肽选择性抑制剂。这些非天然的类似物可以允许选择性地 干扰特定的异戊二烯化靶点，并可能提供先导化合物以减轻潜在的毒性 与蛋白质异戊二烯化的完全抑制相关。特别地，非天然类似物可以是有用的， 为了更全面地了解异戊烯化在法尼基转移酶中的作用， 抑制剂（FTI）逃避癌基因，如K-Ras。对于理解现有药物的临床效果至关重要， 和未来的FTIs和香叶基香叶基转移酶抑制剂（GGTI），是确定体内底物的 FTase和GGT酶-I。我们的创新策略是使用非天然的，可转移的异戊二烯类似物和类似物 鉴定异戊二烯化细胞蛋白的特异性单克隆抗体将提供关于 异戊二烯化抑制剂的细胞靶点。我们希望这些研究能够识别出以前的 未知的异戊二烯化蛋白质本课题的具体目标是：1）法呢基和香叶基香叶基的合成 二磷酸类似物来研究蛋白质异戊二烯化。2)筛选这些化合物的底物特异性 FTase和GGTase-I以及异戊二烯功能抑制剂的开发。3)异戊烯化蛋白的鉴定 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， 分子靶点来开发抗癌疗法。大量证据表明，通常由异戊二烯基修饰的蛋白质在癌症中起着核心作用 进展我们建议设计和测试异戊二烯功能抑制剂，并确定和表征蛋白质 被异戊烯基修饰过。这些研究的结果可能会导致新的分子， 治疗癌症，并确定新的分子靶点，以开发未来的抗癌疗法。

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.