• 中国中文核心期刊
  • 中国科学引文数据库核心期刊
  • 中国科技核心期刊
  • 中国高校百佳科技期刊
高级检索

乙酰辅酶A羧化酶抑制剂的研究进展

梅连阔, 魏强强, 张惠斌, 周金培

梅连阔, 魏强强, 张惠斌, 周金培. 乙酰辅酶A羧化酶抑制剂的研究进展[J]. 中国药科大学学报, 2019, 50(3): 253-264. DOI: 10.11665/j.issn.1000-5048.20190301
引用本文: 梅连阔, 魏强强, 张惠斌, 周金培. 乙酰辅酶A羧化酶抑制剂的研究进展[J]. 中国药科大学学报, 2019, 50(3): 253-264. DOI: 10.11665/j.issn.1000-5048.20190301
MEI Liankuo, WEI Qiangqiang, ZHANG Huibin, ZHOU Jinpei. Research progress in acetyl-CoA carboxylase inhibitors[J]. Journal of China Pharmaceutical University, 2019, 50(3): 253-264. DOI: 10.11665/j.issn.1000-5048.20190301
Citation: MEI Liankuo, WEI Qiangqiang, ZHANG Huibin, ZHOU Jinpei. Research progress in acetyl-CoA carboxylase inhibitors[J]. Journal of China Pharmaceutical University, 2019, 50(3): 253-264. DOI: 10.11665/j.issn.1000-5048.20190301

乙酰辅酶A羧化酶抑制剂的研究进展

基金项目: “重大新药创制”国家科技重大专项资助项目(No.2013ZX09301303-002)

Research progress in acetyl-CoA carboxylase inhibitors

  • 摘要: 非酒精性脂肪肝病是以肝细胞内脂肪过度沉积为主要特征的代谢性疾病,脂肪主要以甘油三酯的形式存在,由甘油和脂肪酸通过酯化作用形成;而且肿瘤细胞中脂肪酸的合成异常活跃,明显高于正常细胞,为肿瘤细胞旺盛的增殖、发育过程中生物膜的形成、信号分子和能量的产生提供必要的脂质底物。乙酰辅酶A羧化酶(acetyl-CoA carboxylase,ACC)是脂肪酸从头合成过程的限速酶,同时也是催化该脂肪酸合成通路中第一步反应的酶;其催化生成的产物丙二酰辅酶A亦能抑制脂肪酸的氧化。因此,ACC抑制能降低脂肪酸合成和促进脂肪酸氧化,降低体内脂肪酸的含量,进而减弱肝细胞内脂肪的堆积来达到改善非酒精性脂肪肝病;同时体内脂肪酸含量的降低使肿瘤细胞发育所必须的脂质底物得不到满足,从而能够抑制肿瘤组织的发育,所以乙酰辅酶A羧化酶抑制剂有望成为新型治疗非酒精性脂肪肝病和肿瘤的药物。本文对ACC的结构特点、作用机制及其抑制剂的研究进展进行了综述。
    Abstract: Non-alcoholic fatty liver disease(NAFLD)is characterized by excessive fat deposition in hepatocytes, fat accumulates mainly in the form of triglycerides, triglycerides derive from esterification of glycerol and free fatty acids; and the synthesis of fatty acid is abnormally active in tumor cells, which is significantly higher than that of normal cells, providing necessary lipid substrates for the formation of biofilms, the production of signaling molecules and energy during the proliferation and development of tumor cells. Acetyl-CoA carboxylase(ACC)is the limiting-rate enzyme of de novo lipogenesis. And it is also an enzyme that catalyzes the first step of the fatty acid synthesis pathway; its catalyzed product, malonyl-CoA, also inhibits the oxidation of fatty acids. ACC inhibition can reduce fatty acid synthesis and promote fatty acid oxidation, which reduce the amount of fatty acids in the body. Hence, attenuating fat accumulation could improve NAFLD, and reduction of fatty acid content inhibits development of tumor tissues because lipid substrates could not satisfy the requirement of cancer cells. Therefore, ACC inhibitors have potential to be the novel drugs that can treat NAFLD and cancer. The recent research progress on ACC inhibitors is reviewed in this paper.
  • [1] Pascale A,Pais R,Ratziu V,et al.An overview of nonalcoholic steatohepatitis:past,present and future directions[J].J Gastrointestin Liver Dis,2010,19(4):415-423.
    [2] Fan JG.Epidemiology of alcoholic and nonalcoholic fatty liver disease in China[J].J Gastroenterol Hepatol,2013,28(Suppl 1):11-17.
    [3] Feldstein AE,Charatcharoenwitthaya P,Treeprasertsuk S,et al.The natural history of non-alcoholic fatty liver disease in children:a follow-up study for up to 20 years[J].Gut,2009,58(11):1538-1544.
    [4] Wattacheril J,Issa D,Sanyal A,et al.Nonalcoholic steatohepatitis(NASH)and hepatic fibrosis:emerging therapies[J].Annu Rev Pharmacol Toxicol,2018,58(1):649-662.
    [5] Fabbrini E,Sullivan S,Klein S,et al.Obesity and nonalcoholic fatty liver disease:biochemical,metabolic,and clinical implications[J].Hepatology,2010,51(2):679-689.
    [6] Medes G,Thomas A,Weinhouse S,et al.Metabolism of neoplastia tissue.IV.A study of lipid synthesis in neoplastia tissue slices in vitro[J].Cancer Res,1953,13(1):27-29.
    [7] Currie E,Schulze A,Zechner R,et al.Cellular fatty acid metabolism and cancer[J].Cell Metab,2013,18(2):153-161.
    [8] Mounier C,Bouraoui L,Rassart E,et al.Lipogenesis in cancer progression[J].Int J Oncol,2014,45(2):485-492.
    [9] Kim J,DeBerardinis RJ.Blocking fatty acid synthesis reduces lung tumor growth in mice[J].Nature Medicine,2016,22(10):1077-1078.
    [10] Martinez UE,Peiris M,Pestell RG,et al.Cancer metabolism:a therapeutic perspective[J].Nat Rev Clin Oncol,2017,14(1):11-31.
    [11] Samuel VT,Shulman GI.Nonalcoholic fatty liver disease as a nexus of metabolic and hepatic diseases[J].Cell Metab,2018,27(1):22-41.
    [12] Francis P.Kuhajda M.Fatty-acid synthase and human cancer:new perspectives on its role in tumor biology[J].Nutrition,2000,16(3):202-208.
    [13] Blank HM,Maitra M,Polymenis M,et al.Lipid biosynthesis:when the cell cycle meets protein synthesis[J].Cell Cycle,2017,16(10):905-906.
    [14] Yu LP,Kim YS,Tong L,et al.Mechanism for the inhibition of the carboxyltransferase domain of acetyl-coenzyme A carboxylase by pinoxaden[J].Proc Natl Acad Sci U S A,2010,107(51):22072-22077.
    [15] Zhang H,Tweel B,Tong L,et al.Molecular basis for the inhibition of the carboxyltransferase domain of acetyl-coenzyme-A carboxylase by haloxyfop and diclofop[J].Proc Natl Acad Sci U S A,2004,101(16):5910-5915.
    [16] Zhang H,Yang Z,Shen Y,et al.Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase[J].Science,2003,299(5615):2064-2067.
    [17] Corbett JW,Freeman-Cook KD,Elliott R,et al.Discovery of small molecule isozyme non-specific inhibitors of mammalian acetyl-CoA carboxylase 1 and 2[J].Bioorg Med Chem Lett,2010,20(7):2383-2388.
    [18] Tong L. Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery[J].Cell Mol Life Sci,2005,62(16):1784-1803.
    [19] Tong L,Harwood HJ Jr.Acetyl-coenzyme A carboxylases:versatile targets for drug discovery[J].J Cell Biochem,2006,99(6):1476-1488.
    [20] Fullerton MD,Galic S,Marcinko K,et al.Single phosphorylation sites in ACC1 and ACC2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin[J].Nat Med,2013,19(12):1649-1654.
    [21] Bengtsson C,Blaho S,Saitton DB,et al.Design of small molecule inhibitors of acetyl-CoA carboxylase 1 and 2 showing reduction of hepatic malonyl-CoA levels in vivo in obese Zucker rats[J].Bioorg Med Chem,2011,19(10):3039-3053.
    [22] Mcgarry JD,Leatherman GF,Foster DW,et al.Carnitine palmitoyltransferase 1.the site of inhibition of hepatic fatty acid oxidation by malonyl-CoA[J].J Biol Chem,1978,253(12):4128-4136.
    [23] Cho YS,Lee JI,Shin D,et al.Molecular mechanism for the regulation of human ACC2 through phosphorylation by AMPK[J].Biochem Biophys Res Commun,2010,391(1):187-192.
    [24] Harwood HJ.Treating the metabolic syndrome:acetyl-CoA carboxylase inhibition[J].Expert Opin 2005,9(2):267-281.
    [25] Shen Y, Volrath SL, Weatherly SC, et al. A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A,a macrocyclic polyketide natural product[J].Mol Cell,2004,16(6):881-891.
    [26] Harwood HJ Jr.,Petras SF,Shelly LD,et al.Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations,inhibit fatty acid synthesis,and increase fatty acid oxidation in cultured cells and in experimental animals[J].J Biol Chem,2003,278(39):37099-37111.
    [27] Zhang H,Tweel B,Li J,et al.Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase in complex with CP-640186[J].Structure,2004,12(9):1683-1691.
    [28] Griffith DA,Kung DW,Esler WP,et al.Decreasing the rate of metabolic ketone reduction in the discovery of a clinical acetyl-CoA carboxylase inhibitor for the treatment of diabetes[J].J Med Chem,2014,57(24):10512-10526.
    [29] Kim CW, Addy C, Kusunoki J, et al. Acetyl CoA carboxylase inhibition reduces hepatic steatosis but elevates plasma triglycerides in mice and humans:a bedside to bench investigation[J].Cell Metab,2017,26(2):394-406.
    [30] Abel R,Mondal S,Masse C,et al.Accelerating drug discovery through tight integration of expert molecular design and predictive scoring[J].Curr Opin Struct Biol,2017,43:38-44.
    [31] Harriman G,Greenwood J,Bhat S,et al.Acetyl-CoA carboxylase inhibition by ND-630 reduces hepatic steatosis,improves insulin sensitivity,and modulates dyslipidemia in rats[J].PNAS,2016,113(13):E1976-E1805.
    [32] Svensson RU,Parker SJ,Eichner LJ,et al.Inhibition of acetyl-CoA carboxylase suppresses fatty acid synthesis and tumor growth of non-small-cell lung cancer in preclinical models[J].Nat Med,2016,22(10):1108-1119.
    [33] Lally JSV,Ghoshal S,DePeralta DK,et al.Inhibition of acetyl-CoA carboxylase by phosphorylation or the inhibitor ND-654 suppresses lipogenesis and hepatocellular carcinoma[J].Cell Metab,2018,29(1):1-9.
    [34] Ratner M.Gilead bets big on Nimbus′ fatty liver disease drug[J].Nat Biotechnol,2016,34(6):575-576.
    [35] Stiede K,Miao W,Blanchette HS,et al.Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects:a randomized,double-blind,crossover study[J].Hepatology,2017,66(2):324-334.
    [36] Loomba R,Kayali Z,Noureddin M,et al.GS-0976 reduces hepatic steatosis and fibrosis markers in patients with nonalcoholic fatty liver disease[J].Gastroenterology,2018,155(5):1463-1473.
    [37] Petrova E,Scholz A,Paul J,et al.Acetyl-CoA carboxylase inhibitors attenuate WNT and Hedgehog signaling and suppress pancreatic tumor growth[J].Oncotarget,2017,8(30):48660-48670.
    [38] Yamashita T,Kamata M,Endo S,et al.Design,synthesis,and structure-activity relationships of spirolactones bearing 2-ureidobenzothiophene as acetyl-CoA carboxylases inhibitors[J].Bioorg Med Chem Lett,2011,21(21):6314-6318.
    [39] Kamata M,Yamashita T,Kina A,et al.Design,synthesis,and structure-activity relationships of novel spiro-piperidines as acetyl-CoA carboxylase inhibitors[J].Bioorg Med Chem Lett,2012,22(11):3643-3647.
    [40] Kamata M,Yamashita T,Kina A,et al.Symmetrical approach of spiro-pyrazolidinediones as acetyl-CoA carboxylase inhibitors[J].Bioorg Med Chem Lett,2012,22(14):4769-4772.
    [41] Mizojiri R,Asano M,Tomita D,et al.Discovery of novel selective acetyl-CoA carboxylase(ACC)1 inhibitors[J].J Med Chem,2018,61(3):1098-1117.
    [42] Chonan T,Tanaka H,Yamamoto D,et al.Design and synthesis of disubstituted(4-piperidinyl)-piperazine derivatives as potent acetyl-CoA carboxylase inhibitors[J].Bioorg Med Chem Lett,2010,20(13):3965-3968.
    [43] Chonan T,Wakasugi D,Yamamoto D,et al.Discovery of novel(4-piperidinyl)-piperazines as potent and orally active acetyl-CoA carboxylase 1/2 non-selective inhibitors:F-Boc and triF-Boc groups are acid-stable bioisosteres for the Boc group[J].Bioorg Med Chem,2011,19(5):1580-1593.
    [44] Keil S,Muller M,Zoller G,et al.Identification and synthesis of novel inhibitors of acetyl-CoA carboxylase with in vitro and in vivo efficacy on fat oxidation[J].J Med Chem,2010,53(24):8679-8687.
    [45] Lovering F,Bikker J,Humblet C,et al..Escape from flatland:increasing saturation as an approach to improving clinical success[J].J Med Chem,2009,52(21):6752-6756.
    [46] Bourbeau MP,Siegmund A,Allen JG,et al.Piperazine oxadiazole inhibitors of acetyl-CoA carboxylase[J].J Med Chem,2013,56(24):10132-10141.
    [47] Nishiura Y, Matsumura A, Kobayashi N, et al. Discovery of a novel olefin derivative as a highly potent and selective acetyl-CoA carboxylase 2 inhibitor with in vivo efficacy[J].Bioorg Med Chem Lett,2018,28(14):2498-2503.
    [48] Jasmina M,Dominika C,Caroline P,et al.Recombinant yeast screen for new inhibitors of human acetyl-CoA carboxylase 2 identifies potential drugs to treat obesity[J].PNAS,2010,107(20):9093-9098.
    [49] Jump DB,Torres-Gonzalez M,Olson LK,et al.Soraphen A,an inhibitor of acetyl CoA carboxylase activity,interferes with fatty acid elongation[J].Biochem Pharmacol,2011,81(5):649-660.
  • 期刊类型引用(10)

    1. 陈俊锟,崔晚香,卜庆,万佩里,姚励功,梁林富,郭跃伟. 短指软珊瑚Sinularia sp.的多骨架类型萜类成分和生物活性研究. 中草药. 2023(05): 1370-1376 . 百度学术
    2. 康华丽,刘俊玲. 非小细胞肺癌组织中THRSP、ACACA的表达及其与临床预后的关系. 实用癌症杂志. 2023(12): 1951-1955 . 百度学术
    3. 吴建美,尉迟邈,尹幸念,钱毅春,樊树理. 马铃薯抗性淀粉对高脂血症大鼠肝脏组织固醇调节元件结合蛋白-1c及裂解激活蛋白以及乙酰辅酶A羧化酶1表达的影响. 环境与健康杂志. 2023(04): 305-309+377 . 百度学术
    4. 杨青,孙子羽,满都拉,王佳,刘瑾,金晶晶,陈忠军. 响应面法优化重组谷氨酸棒杆菌G-BC产脂肪酸的培养条件. 中国油脂. 2022(07): 121-124+131 . 百度学术
    5. 王登杰,王文娟,邹忠兰,张爱华. LXRα/SREBP-1c在砷致大鼠脂代谢紊乱中的作用. 中华地方病学杂志. 2022(07): 517-523 . 百度学术
    6. 吴建民,王建发,武瑞. 瘤胃微生物在奶牛乳脂肪合成中的调节作用研究进展. 中国兽医学报. 2021(01): 181-185 . 百度学术
    7. 杨青,孙子羽,满都拉,王佳,刘瑾,金晶晶,陈忠军. 异源表达乙酰辅酶A羧化酶对大肠杆菌产脂肪酸的影响. 食品研究与开发. 2021(23): 150-155 . 百度学术
    8. 邢海亮,董训赞,韩本勇,耿树香,宁德鲁,马婷,余旭亚. 二氧化碳联合核桃壳提取液促进单针藻Monoraphidium sp.QLZ-3的生长和油脂积累. 化工进展. 2020(04): 1575-1582 . 百度学术
    9. 李硕熙,袁星星,杨磊,李丹丹,王炳予. 基于网络药理学方法分析芪参汤治疗非酒精性脂肪性肝病的作用机制及实验验证. 海南医学院学报. 2020(14): 1074-1082 . 百度学术
    10. 崔佳丽,游金坤,李洁实,乔腾生,董训赞. 核桃壳提取液用于单针藻Monoraphidium sp. QLZ-3培养产油脂. 微生物学报. 2020(11): 2487-2497 . 百度学术

    其他类型引用(12)

计量
  • 文章访问数:  2445
  • HTML全文浏览量:  21
  • PDF下载量:  3459
  • 被引次数: 22
出版历程
  • 刊出日期:  2019-06-24

目录

    /

    返回文章
    返回
    x 关闭 永久关闭