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摘要
溴结构域以特定方式识别并结合组蛋白和非组蛋白中存在的乙酰赖氨酸残基。在过去的十年中,由于人们对人类溴结构域的调控失调与多种疾病的发展有关,它们已成为药物开发的有吸引力的目标。但是,靶向真核病原菌bromodomains仍几乎未被开发。我们和其他人已经报道了原生动物中各种含溴结构域蛋白的必要性,这为抗寄生虫药物的开发提供了新的机遇,特别是恰加斯锥虫病(恰加斯氏病的病原体)。哺乳动物的溴结构域根据序列相似性分为八类,但寄生的溴结构域是非常不同的蛋白质,很难将它们分配给任何这些组,这表明可以得到选择性抑制剂。在这篇综述中,我们描述了T. cruzi中赖氨酸乙酰化和溴结构域的重要性以及关于哺乳动物溴结构域的当前知识。另外,我们总结了正在研究的用于治疗不同病理的无数小分子,其中哪些已在锥虫和其他原生动物中进行了测试。所有可用的信息促使我们提出,应将克鲁氏梭菌溴结构域视为重要的潜在靶标,并应寻求抑制它们的小分子。
关键词: 溴结构域,克氏锥虫,乙酰化,溴结构域抑制剂,恰加斯病,药物发现。
[http://dx.doi.org/10.1016/j.molbiopara.2007.07.007] [PMID: 17765983]
[http://dx.doi.org/10.1128/MMBR.00024-10] [PMID: 21119017]
[http://dx.doi.org/10.1155/2010/525241] [PMID: 20169133]
[http://dx.doi.org/10.1016/j.micinf.2003.09.005] [PMID: 14623019]
[http://dx.doi.org/dx.doi: 10.1042/bse0510031] [PMID: 22023440]
[http://dx.doi.org/10.1016/S1097-2765(03)00143-6] [PMID: 12769852]
[http://dx.doi.org/10.1128/EC.3.2.506-517.2004] [PMID: 15075279]
[http://dx.doi.org/10.1093/nar/gks1469] [PMID: 23361461]
[http://dx.doi.org/10.1371/journal.ppat.1003010] [PMID: 23133390]
[http://dx.doi.org/10.1016/j.molbiopara.2013.09.005] [PMID: 24080031]
[http://dx.doi.org/10.1101/gad.1790409] [PMID: 19369410]
[http://dx.doi.org/10.1016/j.febslet.2006.03.044] [PMID: 16580668]
[http://dx.doi.org/10.1021/acs.jproteome.6b00208] [PMID: 27108550]
[http://dx.doi.org/10.1007/s00412-009-0213-9] [PMID: 19396454]
[http://dx.doi.org/10.1016/j.pt.2007.04.006] [PMID: 17459774]
[http://dx.doi.org/10.1016/j.molbiopara.2007.07.005] [PMID: 17714803]
[http://dx.doi.org/10.1021/acs.jproteome.6b00655] [PMID: 28076955]
[http://dx.doi.org/10.1111/j.1365-3024.2011.01347.x] [PMID: 22132795]
[http://dx.doi.org/10.1074/jbc.M802081200] [PMID: 18400752]
[http://dx.doi.org/10.1186/1471-2164-10-152] [PMID: 19356248]
[http://dx.doi.org/10.1128/EC.05185-11] [PMID: 21926332]
[http://dx.doi.org/10.1155/2012/452934] [PMID: 23093844]
[http://dx.doi.org/10.1111/mmi.12303] [PMID: 23796209]
[http://dx.doi.org/10.1128/EC.00088-12] [PMID: 22544907]
[http://dx.doi.org/10.1021/acs.jproteome.7b00603] [PMID: 29168382]
[http://dx.doi.org/10.1590/S0074-02762009000900014] [PMID: 19753463]
[http://dx.doi.org/10.1590/S0074-02761993000400004] [PMID: 8139463]
[http://dx.doi.org/10.1083/jcb.104.3.431] [PMID: 3818788]
[http://dx.doi.org/10.1146/annurev.mi.41.100187.001015] [PMID: 3120638]
[http://dx.doi.org/10.1042/BJ20150986] [PMID: 26500280]
[http://dx.doi.org/10.1016/0092-8674(92)90191-E] [PMID: 1346755]
[http://dx.doi.org/10.1093/nar/28.1.235] [PMID: 10592235]
[http://dx.doi.org/10.1038/20974] [PMID: 10365964]
[http://dx.doi.org/10.1016/S1097-2765(03)00528-8] [PMID: 14759370]
[http://dx.doi.org/10.1016/j.str.2008.01.010] [PMID: 18400184]
[http://dx.doi.org/10.1016/j.str.2013.10.021] [PMID: 24361270]
[http://dx.doi.org/10.1016/j.cell.2012.02.013] [PMID: 22464331]
[http://dx.doi.org/10.1128/MCB.05413-11] [PMID: 21555453]
[http://dx.doi.org/10.1016/j.bmc.2011.10.080] [PMID: 22137933]
[http://dx.doi.org/10.1038/cr.2010.43] [PMID: 20368734]
[http://dx.doi.org/10.1074/jbc.M109.062422] [PMID: 20048151]
[http://dx.doi.org/10.1093/emboj/19.22.6141] [PMID: 11080160]
[http://dx.doi.org/10.1016/j.bbagrm.2014.03.011] [PMID: 24686119]
[PMID: 19736624]
[http://dx.doi.org/10.1093/nar/gkv1344] [PMID: 26673716]
[http://dx.doi.org/10.1126/science.1063127] [PMID: 11498575]
[http://dx.doi.org/10.1038/nrm.2016.143] [PMID: 28053347]
[http://dx.doi.org/10.1371/journal.ppat.1005366] [PMID: 26727473]
[http://dx.doi.org/10.1016/j.devbrainres.2003.12.011] [PMID: 15063089]
[http://dx.doi.org/10.1002/mrd.20059] [PMID: 15112318]
[http://dx.doi.org/10.1369/jhc.7A7340.2007] [PMID: 18071067]
[http://dx.doi.org/10.1128/MCB.01297-08] [PMID: 18794358]
[http://dx.doi.org/10.1093/emboj/19.15.4123] [PMID: 10921892]
[http://dx.doi.org/10.1016/j.fgb.2015.01.011] [PMID: 25656079]
[http://dx.doi.org/10.1093/molbev/msr121] [PMID: 21546353]
[http://dx.doi.org/10.1128/EC.00341-13] [PMID: 24747213]
[http://dx.doi.org/10.1016/j.ijpara.2008.11.013] [PMID: 19136002]
[http://dx.doi.org/10.1111/febs.13719] [PMID: 27007774]
[http://dx.doi.org/10.1016/j.exppara.2012.01.020] [PMID: 22343032]
[http://dx.doi.org/10.1016/j.bbamcr.2015.09.015] [PMID: 26384872]
[http://dx.doi.org/10.1126/science.1179689] [PMID: 20167786]
[http://dx.doi.org/10.2741/Horn] [PMID: 11487477]
[http://dx.doi.org/10.1042/BCJ20170619] [PMID: 29025975]
[http://dx.doi.org/10.1371/journal.pbio.1002316] [PMID: 26646171]
[http://dx.doi.org/10.1093/nar/gks813] [PMID: 22941664]
[http://dx.doi.org/10.1038/nchembio.2007.18] [PMID: 17643111]
[http://dx.doi.org/10.1038/nchembio.2007.16] [PMID: 17643112]
[http://dx.doi.org/10.1038/nature09504] [PMID: 20871596]
[http://dx.doi.org/10.1021/jm200108t] [PMID: 21568322]
[http://dx.doi.org/10.1038/nature10509] [PMID: 21964340]
[http://dx.doi.org/10.1177/1087057111421372] [PMID: 21956175]
[http://dx.doi.org/10.1016/j.chembiol.2010.12.021] [PMID: 21513889]
[http://dx.doi.org/10.1126/science.274.5292.1531] [PMID: 8929414]
[http://dx.doi.org/10.2174/156802607782341073] [PMID: 17979772]
[http://dx.doi.org/10.1038/nprot.2007.321] [PMID: 17853878]
[http://dx.doi.org/10.1073/pnas.0708800104] [PMID: 18077363]
[http://dx.doi.org/10.1038/nature09589] [PMID: 21068722]
[http://dx.doi.org/10.1039/c1mb05099k] [PMID: 21804994]
[http://dx.doi.org/10.1039/C7MD00083A] [PMID: 30108844]
[http://dx.doi.org/10.1517/13543776.2014.859244] [PMID: 24261714]
[http://dx.doi.org/10.1021/jm201283q] [PMID: 22136469]
[http://dx.doi.org/10.1021/ja107761h] [PMID: 21271695]
[http://dx.doi.org/10.1002/cmdc.201300499] [PMID: 24474698]
[http://dx.doi.org/10.1111/febs.13719] [PMID: 27007774]
[http://dx.doi.org/10.1021/acscombsci.7b00172] [PMID: 29481050]
[http://dx.doi.org/10.1021/acsmedchemlett.8b00247] [PMID: 30344907]
[http://dx.doi.org/10.1016/j.bmcl.2012.01.125] [PMID: 22386529]
[http://dx.doi.org/10.1016/j.chembiol.2011.02.009] [PMID: 21513886]
[http://dx.doi.org/10.1186/1756-8935-7-14] [PMID: 25097667]
[http://dx.doi.org/10.1093/bioinformatics/btu052] [PMID: 24470572]
[http://dx.doi.org/10.1021/jm300915b] [PMID: 22924434]
[http://dx.doi.org/10.1021/cb500996u] [PMID: 25549280]
[http://dx.doi.org/10.1016/j.cbpa.2016.05.028] [PMID: 27295577]
[http://dx.doi.org/10.1021/jm401088k] [PMID: 24015967]
[http://dx.doi.org/10.1021/jm5010539] [PMID: 25249180]
[http://dx.doi.org/10.18632/oncotarget.4131] [PMID: 25989842]
[http://dx.doi.org/10.1038/cddis.2014.396] [PMID: 25299775]
[http://dx.doi.org/10.1021/jm4014407] [PMID: 24107192]
[http://dx.doi.org/10.1158/1541-7786.MCR-15-0472] [PMID: 26792867]
[http://dx.doi.org/10.1002/ijc.30256] [PMID: 27388964]
[http://dx.doi.org/10.1007/s40262-015-0327-6] [PMID: 26341814]
[http://dx.doi.org/10.1038/leu.2014.106] [PMID: 24721791]
[http://dx.doi.org/10.1016/j.cell.2013.05.041] [PMID: 23791182]
[http://dx.doi.org/10.1021/ja412434f] [PMID: 24946055]
[http://dx.doi.org/10.1073/pnas.1501956112] [PMID: 26261308]
[http://dx.doi.org/10.1016/j.bmcl.2012.02.041] [PMID: 22437115]
[http://dx.doi.org/10.1158/2159-8290.CD-12-0418] [PMID: 23430699]
[http://dx.doi.org/10.1128/mSphere.00229-16] [PMID: 28168222]
[http://dx.doi.org/10.1016/j.jacc.2010.02.035] [PMID: 20513599]
[http://dx.doi.org/10.1073/pnas.1310658110] [PMID: 24248379]
[http://dx.doi.org/10.1021/jm3010515] [PMID: 23095041]
[http://dx.doi.org/10.1158/0008-5472.CAN-12-3292] [PMID: 23576556]
[http://dx.doi.org/10.1021/acs.jmedchem.5b00209] [PMID: 25799074]
[http://dx.doi.org/10.1126/sciadv.1600760] [PMID: 27757418]
[http://dx.doi.org/10.1021/jm401568s] [PMID: 24313754]
[http://dx.doi.org/10.18632/oncotarget.21585] [PMID: 29212213]
[http://dx.doi.org/10.1021/acs.jmedchem.5b01882] [PMID: 26815195]
[http://dx.doi.org/10.1038/leu.2016.355] [PMID: 27890933]
[http://dx.doi.org/10.1021/acs.jmedchem.7b00746] [PMID: 28949521]
[http://dx.doi.org/10.1158/1538-7445.AM2017-5080]
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