原虫的bromodomain研究进展
|
摘要
原生动物寄生虫感染是当今全球面临的最紧迫的健康问题之一,且某些种类寄生虫可造成巨大的经济损失。耐药性寄生虫的不断产生,迫切需要揭示其分子致病机理,希望找到新的潜在药物靶点。通过干扰赖氨酸乙酰化破坏基因表达对原生动物寄生虫(疟原虫、弓形虫、锥虫等)的存活具有重要影响,赖氨酸乙酰化的bromodomain蛋白已经成为基因表达的关键调控因子,甚至有希望成为新一类药物靶标。虫体bromodomain蛋白质在寄生虫的生存活力、侵袭和生长阶段转换中发挥重要作用,并且bromodomain抑制剂具有作为新型抗寄生虫药的功效。论文对代表性寄生虫的bromodomain蛋白等相关方面的研究进展做一综述。
Protozoan parasite infections are one of the most pressing global health concerns in the world,and certain types of parasites can cause huge economic losses.The rise of drug-resistant parasites has created an urgent need to explain the molecular pathogenesis in hopes of discovering novel potential drug targets.Researches show that disrupting gene expression by interfering with lysine acetylation is harmful to survival of kinetoplastid parasitics(Plasmodiumspp.,Toxoplasma gondii,Trypanosomaspp.).Lysine acetylated bromodomain proteins have become key regulators of gene expression and may even be a new class of drug targets.It is shown that bromodomain proteins play an important role in parasite viability,invasion,stage switching,and bromodomain inhibitors bring about a striking effect of novel antiparasitic agents.In this article,we reviewed the research progress on bromodomain proteins in representative parasites.
Protozoan parasite infections are one of the most pressing global health concerns in the world,and certain types of parasites can cause huge economic losses.The rise of drug-resistant parasites has created an urgent need to explain the molecular pathogenesis in hopes of discovering novel potential drug targets.Researches show that disrupting gene expression by interfering with lysine acetylation is harmful to survival of kinetoplastid parasitics(Plasmodiumspp.,Toxoplasma gondii,Trypanosomaspp.).Lysine acetylated bromodomain proteins have become key regulators of gene expression and may even be a new class of drug targets.It is shown that bromodomain proteins play an important role in parasite viability,invasion,stage switching,and bromodomain inhibitors bring about a striking effect of novel antiparasitic agents.In this article,we reviewed the research progress on bromodomain proteins in representative parasites.
引文
[1]Jeffers V,Yang C,Huang S,et al.Bromodomains in protozoan parasites:evolution,function,and opportunities for drug development[J].Microbiol Mol Biol Rev,2017,11;81(1).e00047-16.doi:10.1128/MMBR.
[2]Musselman C A,Lalonde M E,Cote J,et al.Perceiving the epigenetic landscape through histone readers[J].Nat Struct Mol Biol,2012,19(12):1218-1227.
[3]Schulz D,Mugnier M R,Paulsen E M,et al.bromodomain proteins contribute to maintenance of bloodstream form stage identity in the African trypanosome[J].PLoS Biol,2015,13(12):e1002316.
[4]Josling G A,Petter M,Oehring S C,et al.A Plasmodium falciparum bromodomain protein regulates invasion gene expression[J].Cell Host Microbe,2015,17(6):741-751.
[5]Alonso V L,Ritagliati C,Cribb P,et al.Overexpression of bromodomain factor 3in Trypanosoma cruzi(TcBDF3)affects parasite differentiation and protects it against bromodomain inhibitors[J].FEBS J,2016,283:2051-2066.
[6]Darkin-Rattray S J,Gurnett A M,Myers R W,et al.Apicidin:a novel antiprotozoal agent that inhibits parasite histone deacetylase[J].Proc Natl Acad Sci,1996,93:13143-13147.
[7]Engel J A,Jones A J,Avery V M,et al.Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodiumand Trypanosoma parasites[J].Int J Parasitol Drugs Drug Resist,2015(5):117-126.
[8]Jeffers V,Gao H,Checkley L A,et al.Garcinol inhibits GCN5-mediated lysine acetyltransferase activity and prevents replication of the parasite Toxoplasma gondii[J].Antimicrob Agents Chemother,2016,60:2164-2170.
[9]Miao J,Lawrence M,Jeffers V,et al.Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development[J].Mol Microbiol,2013,89:660-675.
[10]Xue B,Jeffers V,Sullivan W J,et al.Protein intrinsic disorder in the acetylome of intracellular and extracellular Toxoplasma gondii[J].Mol Biosyst,2013,9:645-657.
[11]Wang Q,Rosa B A,Nare B,et al.Targeting lysine deacetylases(KDACs)in parasites[J].PLoS Negl Trop Dis,2015,9:e0004026.
[12]Veiga-Santos P,Reignault L C,Huber K,et al.Inhibition of NAD+-dependent histone deacetylases(sirtuins)causes growth arrest and activates both apoptosis and autophagy in the pathogenic protozoan Trypanosoma cruzi[J].Parasitology,2014,141:814-825.
[13]Kanjee U,Grüring C,Chaand M,et al.CRISPR/Cas9knockouts reveal genetic interaction between strain-transcendent erythrocyte determinants of Plasmodium falciparuminvasion[J].Proc Natl Acad Sci,2017,114(44):E9356-E9365.
[14]Josling G A,Petter M,Oehring S C,et al.APlasmodium falciparum bromodomain protein regulates invasion gene expression[J].Cell Host Microbe,2015,17(6):741-51.
[15]Santos J M,Josling G,Ross P,et al.Red blood cell invasion by the malaria parasite is coordinated by the PfAP2-I transcription factor[J].Cell Host Microbe,2017,21(6):731-741.
[16]Chua M J,Robaa D,Skinner-Adams T S,et al.Activity of bromodomain protein inhibitors/binders against asexual-stage Plasmodium falciparum parasites[J].Int J Parasitol Drugs Drug Resist,2018,8(2):189-193.
[17]Wang J,Dixon S E,Ting L M,et al.Lysine acetyltransferase GCN5binteracts with AP2factors and is required for Toxoplasma gondii proliferation[J].PLoS Pathog,2014,10:e1003830.
[18]Filippakopoulos P,Picaud S,Mangos M,et al.Histone recognition and large-scale structural analysis of the human bromodomain family[J].Cell,2012,149:214-231.
[19]Haanstra J R,Gonzalez-Marcano E B,Gualdron-Lopez M,et al.Biogenesis,maintenance and dynamics of glycosomes in trypanosomatid parasites[J].Biochim Biophys Acta,2016,1863:1038-1048.
[20]Ritagliati C,Villanova G V,Alonso V L,et al.Glycosomal bromodomain factor 1fromTrypanosoma cruzi enhances trypomastigote cell infection and intracellular amastigote growth[J].Biochem J,2016,473:73-85.
[21]Siegel T N,Hekstra D R,Kemp L E,et al.Four histone variants mark the boundaries of polycistronic transcription units in Trypanosoma brucei[J].Genes Dev,2009,23:1063-1076.
[22]Yang X,Wu X,Zhang J,et al.Recognition of hyperacetylated N-terminus of H2AZ by TbBDF2from Trypanosoma brucei[J].Biochem J,2017,474(22):3817-3830.
[23]Alsford S,Horn D.Cell-cycle-regulated control of VSG expression site silencing by histones and histone chaperones ASF1Aand CAF-1bin Trypanosoma brucei[J].Nucleic Acids Res,2012,40:10150-10160.
[24]陈金晶,赵晓丽,王真,等.含溴结构域和额外终端域家族蛋白---表观遗传领域的新型治疗靶点[J].药学学报,2017,52(8):1209-1215.
[25]Bharatham N,Slavish P J,Young B M,et al.The role of ZAchannel water-mediated interactions in the design of bromodomain-selective BET inhibitors[J].J Mol Graph Model,2018,81:197-210.
[26]Morse M A,Balogh K K,Brendle S A,et al.BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growthin vivo[J].Antiviral Res,2018,154:158-165.
[27]Jeffers V,Kamau E,Srinivasan A,et al.TgPRELID,a novel mitochondrial protein linked to multi-drug resistance in the parasite Toxoplasma gondii[J].MSphere,2017,2(1):e00229-16.
[28]陈红丽,陈海芳,张智敏,等.基于多向药理学的BET Bromodomain抑制剂及降解剂研究进展[J].国际药学研究杂志,2017,44(6):471-479,486.
[2]Musselman C A,Lalonde M E,Cote J,et al.Perceiving the epigenetic landscape through histone readers[J].Nat Struct Mol Biol,2012,19(12):1218-1227.
[3]Schulz D,Mugnier M R,Paulsen E M,et al.bromodomain proteins contribute to maintenance of bloodstream form stage identity in the African trypanosome[J].PLoS Biol,2015,13(12):e1002316.
[4]Josling G A,Petter M,Oehring S C,et al.A Plasmodium falciparum bromodomain protein regulates invasion gene expression[J].Cell Host Microbe,2015,17(6):741-751.
[5]Alonso V L,Ritagliati C,Cribb P,et al.Overexpression of bromodomain factor 3in Trypanosoma cruzi(TcBDF3)affects parasite differentiation and protects it against bromodomain inhibitors[J].FEBS J,2016,283:2051-2066.
[6]Darkin-Rattray S J,Gurnett A M,Myers R W,et al.Apicidin:a novel antiprotozoal agent that inhibits parasite histone deacetylase[J].Proc Natl Acad Sci,1996,93:13143-13147.
[7]Engel J A,Jones A J,Avery V M,et al.Profiling the anti-protozoal activity of anti-cancer HDAC inhibitors against Plasmodiumand Trypanosoma parasites[J].Int J Parasitol Drugs Drug Resist,2015(5):117-126.
[8]Jeffers V,Gao H,Checkley L A,et al.Garcinol inhibits GCN5-mediated lysine acetyltransferase activity and prevents replication of the parasite Toxoplasma gondii[J].Antimicrob Agents Chemother,2016,60:2164-2170.
[9]Miao J,Lawrence M,Jeffers V,et al.Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development[J].Mol Microbiol,2013,89:660-675.
[10]Xue B,Jeffers V,Sullivan W J,et al.Protein intrinsic disorder in the acetylome of intracellular and extracellular Toxoplasma gondii[J].Mol Biosyst,2013,9:645-657.
[11]Wang Q,Rosa B A,Nare B,et al.Targeting lysine deacetylases(KDACs)in parasites[J].PLoS Negl Trop Dis,2015,9:e0004026.
[12]Veiga-Santos P,Reignault L C,Huber K,et al.Inhibition of NAD+-dependent histone deacetylases(sirtuins)causes growth arrest and activates both apoptosis and autophagy in the pathogenic protozoan Trypanosoma cruzi[J].Parasitology,2014,141:814-825.
[13]Kanjee U,Grüring C,Chaand M,et al.CRISPR/Cas9knockouts reveal genetic interaction between strain-transcendent erythrocyte determinants of Plasmodium falciparuminvasion[J].Proc Natl Acad Sci,2017,114(44):E9356-E9365.
[14]Josling G A,Petter M,Oehring S C,et al.APlasmodium falciparum bromodomain protein regulates invasion gene expression[J].Cell Host Microbe,2015,17(6):741-51.
[15]Santos J M,Josling G,Ross P,et al.Red blood cell invasion by the malaria parasite is coordinated by the PfAP2-I transcription factor[J].Cell Host Microbe,2017,21(6):731-741.
[16]Chua M J,Robaa D,Skinner-Adams T S,et al.Activity of bromodomain protein inhibitors/binders against asexual-stage Plasmodium falciparum parasites[J].Int J Parasitol Drugs Drug Resist,2018,8(2):189-193.
[17]Wang J,Dixon S E,Ting L M,et al.Lysine acetyltransferase GCN5binteracts with AP2factors and is required for Toxoplasma gondii proliferation[J].PLoS Pathog,2014,10:e1003830.
[18]Filippakopoulos P,Picaud S,Mangos M,et al.Histone recognition and large-scale structural analysis of the human bromodomain family[J].Cell,2012,149:214-231.
[19]Haanstra J R,Gonzalez-Marcano E B,Gualdron-Lopez M,et al.Biogenesis,maintenance and dynamics of glycosomes in trypanosomatid parasites[J].Biochim Biophys Acta,2016,1863:1038-1048.
[20]Ritagliati C,Villanova G V,Alonso V L,et al.Glycosomal bromodomain factor 1fromTrypanosoma cruzi enhances trypomastigote cell infection and intracellular amastigote growth[J].Biochem J,2016,473:73-85.
[21]Siegel T N,Hekstra D R,Kemp L E,et al.Four histone variants mark the boundaries of polycistronic transcription units in Trypanosoma brucei[J].Genes Dev,2009,23:1063-1076.
[22]Yang X,Wu X,Zhang J,et al.Recognition of hyperacetylated N-terminus of H2AZ by TbBDF2from Trypanosoma brucei[J].Biochem J,2017,474(22):3817-3830.
[23]Alsford S,Horn D.Cell-cycle-regulated control of VSG expression site silencing by histones and histone chaperones ASF1Aand CAF-1bin Trypanosoma brucei[J].Nucleic Acids Res,2012,40:10150-10160.
[24]陈金晶,赵晓丽,王真,等.含溴结构域和额外终端域家族蛋白---表观遗传领域的新型治疗靶点[J].药学学报,2017,52(8):1209-1215.
[25]Bharatham N,Slavish P J,Young B M,et al.The role of ZAchannel water-mediated interactions in the design of bromodomain-selective BET inhibitors[J].J Mol Graph Model,2018,81:197-210.
[26]Morse M A,Balogh K K,Brendle S A,et al.BET bromodomain inhibitors show anti-papillomavirus activity in vitro and block CRPV wart growthin vivo[J].Antiviral Res,2018,154:158-165.
[27]Jeffers V,Kamau E,Srinivasan A,et al.TgPRELID,a novel mitochondrial protein linked to multi-drug resistance in the parasite Toxoplasma gondii[J].MSphere,2017,2(1):e00229-16.
[28]陈红丽,陈海芳,张智敏,等.基于多向药理学的BET Bromodomain抑制剂及降解剂研究进展[J].国际药学研究杂志,2017,44(6):471-479,486.