PDZ结构域有望成为新药靶点
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摘要
PDZ结构域是蛋白质中最常见的肽结合区域之一,它涉及许多关键信号通路。以突触后致密蛋白-95(PSD-95) PDZ结构域为靶点,设计合成的Tat-NR2B9C和ZL006,显示神经保护活性;以神经元型一氧化氮合酶(nNOS) PDZ结构域为靶点,设计合成的ZLc-002,显示抗焦虑活性。本文重点介绍PDZ结构域的结构、分类及有望以含PDZ结构域的蛋白为靶点开发出治疗急性缺血性脑卒中和焦虑症的新药。
PDZ domains,which involve many key signaling pathways,are one of the most common peptide binding domains in proteins. Postsynaptic density protein-95( PSD-95) containing PDZ domains can serve as a target for designing and synthesizing Tat-NR2 B9 C and ZL006 which display potent neuroprotective activity. Neuronal nitric oxide synthase( nNOS) containing PDZ domains can serve as a target for designing and synthesizing ZLc-002 which has antianxiety activity. This review focuses on the structure,classification and the potential design of new drugs for the treatment of acute ischemic stroke and anxiety by targeting proteins containing PDZ domains.
PDZ domains,which involve many key signaling pathways,are one of the most common peptide binding domains in proteins. Postsynaptic density protein-95( PSD-95) containing PDZ domains can serve as a target for designing and synthesizing Tat-NR2 B9 C and ZL006 which display potent neuroprotective activity. Neuronal nitric oxide synthase( nNOS) containing PDZ domains can serve as a target for designing and synthesizing ZLc-002 which has antianxiety activity. This review focuses on the structure,classification and the potential design of new drugs for the treatment of acute ischemic stroke and anxiety by targeting proteins containing PDZ domains.
引文
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[14] ZHOU L,LI F,XU HB,et al. Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95[J]. Nat Med,2010,16(12):1439-1443.
[15] ZHU LJ,LI TY,LUO CX,et al. Capon-nNOS coupling can serve as a target for developing new anxiolytics[J]. Nat Med,2014,20(9):1050-1054.
[16] NI HY,SONG YX,LIN YH,et al. Dissociating nNOS(neuronal no synthase)-Capon(carboxy-terminal postsynaptic density-95/discs large/zona occludens-1 ligand of nNOS)interaction promotes functional recovery after stroke via enhanced structural neuroplasticity[J]. Stroke,2019,50(3):728-737.
[17] LEE WH,XU Z,ASHPOLE NM,et al. Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics[J]. Neuropharmacology,2015,97:464-475.
[18] LI LP,DUSTRUDE ET,HAULCOMB MM,et al. PSD95 and nNOS interaction as a novel molecular target to modulate conditioned fear:relevance to PTSD[J]. Transl Psychiat,2018,8(1):155-167.
[19] ZHOU HH,TANG Y,ZHANG XY,et al. Delayed administration of Tat-HA-NR2B9c promotes recovery after stroke in rats[J]. Stroke,2015,46(5):1352-1358.
[20] ITTNER LM,KE YD,DELERUE F,et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models[J]. Cell,2010,142(3):387-397.
[21] DYKSTRA CM,RATNAM M,GURD JW. Neuroprotection after status epilepticus by targeting protein interactions with postsynaptic density protein 95[J]. J Neuropathol Exp Neurol,2009,68(7):823-831.
[2] KHAN Z,LAFON M. PDZ domain-mediated protein interactions:therapeutic targets in neurological disorders[J]. Curr Med Chem,2014,21(23):2632-2641.
[3] LI J,HE Y,WECK ML,et al. Structure of Myo7b/USH1C complex suggests a general PDZ domain binding mode by My TH4-FERM myosins[J]. Proc Natl Acad Sci USA,2017,114(19):E3776-E3785.
[4] PINCUS D,RESNEKOV O,REYNOLDS KA. An evolutionbased strategy for engineering allosteric regulation[J]. Phys Biol,2017,14(2):025002.
[5] GARRIDO-URBANI S,GARG P,GHOSSOUB R,et al. Proteomic peptide phage display uncovers novel interactions of the PDZ1-2 supramodule of syntenin[J]. Febs Lett,2016,590(1):3-12.
[6] MOORE CD,AJALA OZ,ZHU H. Applications in high-content functional protein microarrays[J]. Curr Opin Chem Biol,2016,30:21-27.
[7] IVARSSON Y,ARNOLD R,MCLAUGHLIN M,et al. Largescale interaction profiling of PDZ domains through proteomic peptide-phage display using human and viral phage peptidomes[J].P Natl Acad Sci USA,2014,111(7):2542-2547.
[8] TURNER KB,NACIRI J,LIU JL,et al. Next-generation sequencing of a single domain antibody repertoire reveals quality of phage display selected candidates[J]. Plos One,2016,11(2):e0149393.
[9] HARDINGHAM GE,BADING H. Synaptic versus extrasynaptic NMDA receptor signalling:implications for neurodegenerative disorders[J]. Nat Rev Neurosci,2010,11(10):682-696.
[10] BALLARIN B,TYMIANSKI M. Discovery and development of NA-1 for the treatment of acute ischemic stroke[J]. Acta Pharmacol Sin,2018,39(5):661-668.
[11] AARTS M,LIU Y,LIU L,et al. Treatment of ischemic brain damage by perturbing NMDA receptor-PSD-95 protein interactions[J]. Science,2002,298(5594):846-850.
[12] COOK DJ,TEVES L,TYMIANSKI M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain[J]. Nature,2012,483(7388):213-217.
[13] HILL MD,MARTIN RH,MIKULIS D,et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair(ENACT):a phase 2,randomised,double-blind,placebo-controlled trial[J]. Lancet Neurol,2012,11(11):942-950.
[14] ZHOU L,LI F,XU HB,et al. Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95[J]. Nat Med,2010,16(12):1439-1443.
[15] ZHU LJ,LI TY,LUO CX,et al. Capon-nNOS coupling can serve as a target for developing new anxiolytics[J]. Nat Med,2014,20(9):1050-1054.
[16] NI HY,SONG YX,LIN YH,et al. Dissociating nNOS(neuronal no synthase)-Capon(carboxy-terminal postsynaptic density-95/discs large/zona occludens-1 ligand of nNOS)interaction promotes functional recovery after stroke via enhanced structural neuroplasticity[J]. Stroke,2019,50(3):728-737.
[17] LEE WH,XU Z,ASHPOLE NM,et al. Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics[J]. Neuropharmacology,2015,97:464-475.
[18] LI LP,DUSTRUDE ET,HAULCOMB MM,et al. PSD95 and nNOS interaction as a novel molecular target to modulate conditioned fear:relevance to PTSD[J]. Transl Psychiat,2018,8(1):155-167.
[19] ZHOU HH,TANG Y,ZHANG XY,et al. Delayed administration of Tat-HA-NR2B9c promotes recovery after stroke in rats[J]. Stroke,2015,46(5):1352-1358.
[20] ITTNER LM,KE YD,DELERUE F,et al. Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models[J]. Cell,2010,142(3):387-397.
[21] DYKSTRA CM,RATNAM M,GURD JW. Neuroprotection after status epilepticus by targeting protein interactions with postsynaptic density protein 95[J]. J Neuropathol Exp Neurol,2009,68(7):823-831.