凝血酶GPIb-Ⅸ-Ⅴ受体作用机制及相关药物研究进展
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摘要
凝血酶是凝血瀑布中的重要位点,在止血与凝血中扮演着重要角色。凝血酶与血小板膜受体GPIb-Ⅸ-Ⅴ结合可以介导血小板活化,促进血栓生成。本文通过查阅相关文献,对凝血酶和GPIb-Ⅸ-Ⅴ受体的结构、作用机制进行相关介绍,并将近年来针对凝血酶和GPIb-Ⅸ-Ⅴ受体为治疗靶点的新型抗血栓制剂进行综述,期望对血栓治疗提供新思路。
Thrombin,a key factor of the coagulation cascade,plays an important role on hemostasis and coagulation.Thrombin binding to platelet membrane receptor GPIb-Ⅸ-Ⅴ can mediate platelet activation and promote thrombosis.By reviewing the relevant literatures,we introduce the structure of thrombin and GPIb-Ⅸ-Ⅴ complex and the mechanisms of its interaction.Moreover,this paper reviewed the latest study progress of novel anti-thrombotic agents targeting on thrombin or GPIb-Ⅸ-Ⅴ to provide new ideas for thrombus therapy.
Thrombin,a key factor of the coagulation cascade,plays an important role on hemostasis and coagulation.Thrombin binding to platelet membrane receptor GPIb-Ⅸ-Ⅴ can mediate platelet activation and promote thrombosis.By reviewing the relevant literatures,we introduce the structure of thrombin and GPIb-Ⅸ-Ⅴ complex and the mechanisms of its interaction.Moreover,this paper reviewed the latest study progress of novel anti-thrombotic agents targeting on thrombin or GPIb-Ⅸ-Ⅴ to provide new ideas for thrombus therapy.
引文
[1]MEHTA A Y,THAKKAR J N,MOHAMMED B M,et al.Targeting the GPIbalpha binding site of thrombin to simultaneously induce dual anticoagulant and antiplatelet effects[J].J Med Chem,2014,57(7):3030-3039.
[2]TRAPAIDZE A,HERAULT J P,HERBERT J M,et al.Investigation of the selectivity of thrombin-binding aptamers for thrombin titration in murine plasma[J].Biosens Bioelectron,2016(78):58-66.
[3]REININGER A J.VWF attributes--impact on thrombus formation[J].Thromb Res,2008,122(Suppl 4):S9-13.
[4]COSEMANS J M,SCHOLS S E,STEFANINI L,et al.Key role of glycoprotein Ib/V/IX and von Willebrand factor in platelet activation-dependent fibrin formation at low shear flow[J].Blood,2011,117(2):651-660.
[5]LI R,EMSLEY J.The organizing principle of the platelet glycoprotein Ib-IX-V complex[J].J Thromb Haemost,2013,11(4):605-614.
[6]JU L,LOU J,CHEN Y,et al.Force-Induced Unfolding of Leucine-Rich Repeats of Glycoprotein Ibalpha Strengthens Ligand Interaction[J].Biophys J,2015,109(9):1781-1784.
[7]KRISHNASWAMY S.The transition of prothrombin to thrombin[J].J Thromb Haemost,2013,11(Suppl 1):265-276.
[8]ADAMS T E,HUNTINGTON J A.Structural transitions during prothrombin activation:On the importance of fragment 2[J].Biochimie,2016(122):235-242.
[9]CHAHAL G,THORPE M,HELLMAN L.The Importance of Exosite Interactions for Substrate Cleavage by Human Thrombin[J].Plo S One,2015,10(6):e0129511.
[10]MALOVICHKO M V,SABO T M,MAURER M C.Ligand binding to anion-binding exosites regulates conformational properties of thrombin[J].J Biol Chem,2013,288(12):8667-8678.
[11]HUNTINGTON J A.Natural inhibitors of thrombin[J].Thromb Haemost,2014,111(4):583-589.
[12]LECHTENBERG B C,JOHNSON D J,FREUND S M,et al.NMR resonance assignments of thrombin reveal the conformational and dynamic effects of ligation[J].Proc Natl Acad Sci U S A,2010,107(32):14087-14092.
[13]HANDLEY L D,TREUHEIT N A,VENKATESH V J,et al.Thrombomodulin Binding Selects the Catalytically Active Form of Thrombin[J].Biochemistry,2015,54(43):6650-6658.
[14]ZARPELLON A,CELIKEL R,ROBERTS J R,et al.Binding of alpha-thrombin to surface-anchored platelet glycoprotein Ib(alpha)sulfotyrosines through a two-site mechanism involving exosite I[J].Proc Natl Acad Sci U S A,2011,108(21):8628-8633.
[15]VERHAMME I M.Fluorescent reporters of thrombin,heparin cofactor II,and heparin binding in a ternary complex[J].Anal Biochem,2012,421(2):489-498.
[16]YEH C H,STAFFORD A R,LESLIE B A,et al.Dabigatran and Argatroban Diametrically Modulate Thrombin Exosite Function[J].Plo S One,2016,11(6):e0157471.
[17]KAMATH P,HUNTINGTON J A,KRISHNASWAMY S.Ligand binding shuttles thrombin along a continuum of zymogen-and proteinase-like states[J].J Biol Chem,2010,285(37):28651-28658.
[18]RUGGERI Z M,ZARPELLON A,ROBERTS J R,et al.Unravelling the mechanism and significance of thrombin binding to platelet glycoprotein Ib[J].Thromb Haemost,2010,104(5):894-902.
[19]JANDROT-PERRUS M,DIDRY D,GUILLIN M C,et al.Cross-linking of alpha and gamma-thrombin to distinct binding sites on human platelets[J].Eur J Biochem,1988,174(2):359-367.
[20]JANDROT-PERRUS M,BOUTON M C,LANZA F,et al.Thrombin interaction with platelet membrane glycoprotein Ib[J].Semin Thromb Hemost,1996,22(2):151-156.
[21]DE CANDIA E,DE CRISTOFARO R,DE MARCO L,et al.Thrombin interaction with platelet Gp IB:role of the heparin binding domain[J].Thrombosis and haemostasis,1997,77(4):735-740.
[22]GANDHI P S,CHEN Z,DI CERA E.Crystal structure of thrombin bound to the uncleaved extracellular fragment of PAR1[J].J Biol Chem,2010,285(20):15393-15398.
[23]DE CRISTOFARO R,DE CANDIA E,LANDOLFI R,et al.Structural and functional mapping of the thrombin domain involved in the binding to the platelet glycoprotein Ib[J].Biochemistry,2001,40(44):13268-13273.
[24]DE CANDIA E,DE CRISTOFARO R,DE MARCO L,et al.Thrombin interaction with platelet Gp IB:role of the heparin binding domain[J].Thrombosis and haemostasis,1997,77(4):735-740.
[25]BOYLE A J,RODDICK L A,BHAKTA V,et al.The complete N-terminal extension of heparin cofactor II is required for maximal effectiveness as a thrombin exosite 1ligand[J].BMC Biochem,2013(14):6.
[26]GAGAOUA M,HAFID K,BOUDIDA Y,et al.Caspases and Thrombin Activity Regulation by Specific Serpin Inhibitors in Bovine Skeletal Muscle[J].Appl Biochem Biotechnol,2015,177(2):279-303.
[27]KOUSTED T M,SKJOEDT K,PETERSEN S V,et al.Three monoclonal antibodies against the serpin protease nexin-1 prevent protease translocation[J].Thromb Haemost,2014,111(1):29-40.
[28]LIU Z,YU Z,HUANG Y,et al.A novel stearic acid-modified hirudin peptidomimetic with improved pharmacokinetic properties and anticoagulant activity[J].Sci Rep,2015(5):14349.
[29]KENNEDY B,GARGOUM F S,KENNEDY L,et al.Emerging anticoagulants[J].Curr Med Chem,2012,19(20):3388-3416.
[30]VORA A.Dabigatran etexilate in atrial fibrillation[J].J Assoc Physicians India,2013,61(12):900-902.
[31]DAS A,LIU D.Novel antidotes for target specific oral anticoagulants[J].Exp Hematol Oncol,2015(4):25.
[32]GLUND S,STANGIER J,SCHMOHL M,et al.Safety,tolerability,and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers:a randomised,placebo-controlled,double-blind phase 1 trial[J].Lancet,2015,386(9994):680-690.
[33]ERIKSSON B I,QUINLAN D J,WEITZ J I.Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development[J].Clin Pharmacokinet,2009,48(1):1-22.
[34]ANDERSSON S,HOFMANN Y,NORDLING A,et al.Characterization and partial purification of the rat and human enzyme systems active in the reduction of Nhydroxymelagatran and benzamidoxime[J].Drug metabolism and disposition:the biological fate of chemicals,2005,33(4):570-578.
[35]JOHANSSON S,CULLBERG M,ERIKSSON U G,et al.Single-dose pharmacokinetics,pharmacodynamics and safety of AZD0837,a novel oral direct thrombin inhibitor,in young healthy male subjects[J].Int J Clin Pharmacol Ther,2011,49(4):258-267.
[36]GRESELE P,MOMI S.Inhibitors of the interaction between von Willebrand factor and platelet GPIb/IX/V[J].Handb Exp Pharmacol,2012(210):287-309.
[37]LEI X,REHEMAN A,HOU Y,et al.Anfibatide,a novel GPIb complex antagonist,inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis[J].Thromb Haemost,2014,111(2):279-289.
[38]LI T T,FAN M L,HOU S X,et al.A novel snake venomderived GPIb antagonist,anfibatide,protects mice from acute experimental ischaemic stroke and reperfusion injury[J].British journal of pharmacology,2015,172(15):3904-3916.
[39]FONTAYNE A,MEIRING M,LAMPRECHT S,et al.The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons[J].Thromb Haemost,2008,100(4):670-677.
[40]HENNAN J K,SWILLO R E,MORGAN G A,et al.Pharmacologic inhibition of platelet v WF-GPIb alpha interaction prevents coronary artery thrombosis[J].Thromb Haemost,2006,95(3):469-475.
[2]TRAPAIDZE A,HERAULT J P,HERBERT J M,et al.Investigation of the selectivity of thrombin-binding aptamers for thrombin titration in murine plasma[J].Biosens Bioelectron,2016(78):58-66.
[3]REININGER A J.VWF attributes--impact on thrombus formation[J].Thromb Res,2008,122(Suppl 4):S9-13.
[4]COSEMANS J M,SCHOLS S E,STEFANINI L,et al.Key role of glycoprotein Ib/V/IX and von Willebrand factor in platelet activation-dependent fibrin formation at low shear flow[J].Blood,2011,117(2):651-660.
[5]LI R,EMSLEY J.The organizing principle of the platelet glycoprotein Ib-IX-V complex[J].J Thromb Haemost,2013,11(4):605-614.
[6]JU L,LOU J,CHEN Y,et al.Force-Induced Unfolding of Leucine-Rich Repeats of Glycoprotein Ibalpha Strengthens Ligand Interaction[J].Biophys J,2015,109(9):1781-1784.
[7]KRISHNASWAMY S.The transition of prothrombin to thrombin[J].J Thromb Haemost,2013,11(Suppl 1):265-276.
[8]ADAMS T E,HUNTINGTON J A.Structural transitions during prothrombin activation:On the importance of fragment 2[J].Biochimie,2016(122):235-242.
[9]CHAHAL G,THORPE M,HELLMAN L.The Importance of Exosite Interactions for Substrate Cleavage by Human Thrombin[J].Plo S One,2015,10(6):e0129511.
[10]MALOVICHKO M V,SABO T M,MAURER M C.Ligand binding to anion-binding exosites regulates conformational properties of thrombin[J].J Biol Chem,2013,288(12):8667-8678.
[11]HUNTINGTON J A.Natural inhibitors of thrombin[J].Thromb Haemost,2014,111(4):583-589.
[12]LECHTENBERG B C,JOHNSON D J,FREUND S M,et al.NMR resonance assignments of thrombin reveal the conformational and dynamic effects of ligation[J].Proc Natl Acad Sci U S A,2010,107(32):14087-14092.
[13]HANDLEY L D,TREUHEIT N A,VENKATESH V J,et al.Thrombomodulin Binding Selects the Catalytically Active Form of Thrombin[J].Biochemistry,2015,54(43):6650-6658.
[14]ZARPELLON A,CELIKEL R,ROBERTS J R,et al.Binding of alpha-thrombin to surface-anchored platelet glycoprotein Ib(alpha)sulfotyrosines through a two-site mechanism involving exosite I[J].Proc Natl Acad Sci U S A,2011,108(21):8628-8633.
[15]VERHAMME I M.Fluorescent reporters of thrombin,heparin cofactor II,and heparin binding in a ternary complex[J].Anal Biochem,2012,421(2):489-498.
[16]YEH C H,STAFFORD A R,LESLIE B A,et al.Dabigatran and Argatroban Diametrically Modulate Thrombin Exosite Function[J].Plo S One,2016,11(6):e0157471.
[17]KAMATH P,HUNTINGTON J A,KRISHNASWAMY S.Ligand binding shuttles thrombin along a continuum of zymogen-and proteinase-like states[J].J Biol Chem,2010,285(37):28651-28658.
[18]RUGGERI Z M,ZARPELLON A,ROBERTS J R,et al.Unravelling the mechanism and significance of thrombin binding to platelet glycoprotein Ib[J].Thromb Haemost,2010,104(5):894-902.
[19]JANDROT-PERRUS M,DIDRY D,GUILLIN M C,et al.Cross-linking of alpha and gamma-thrombin to distinct binding sites on human platelets[J].Eur J Biochem,1988,174(2):359-367.
[20]JANDROT-PERRUS M,BOUTON M C,LANZA F,et al.Thrombin interaction with platelet membrane glycoprotein Ib[J].Semin Thromb Hemost,1996,22(2):151-156.
[21]DE CANDIA E,DE CRISTOFARO R,DE MARCO L,et al.Thrombin interaction with platelet Gp IB:role of the heparin binding domain[J].Thrombosis and haemostasis,1997,77(4):735-740.
[22]GANDHI P S,CHEN Z,DI CERA E.Crystal structure of thrombin bound to the uncleaved extracellular fragment of PAR1[J].J Biol Chem,2010,285(20):15393-15398.
[23]DE CRISTOFARO R,DE CANDIA E,LANDOLFI R,et al.Structural and functional mapping of the thrombin domain involved in the binding to the platelet glycoprotein Ib[J].Biochemistry,2001,40(44):13268-13273.
[24]DE CANDIA E,DE CRISTOFARO R,DE MARCO L,et al.Thrombin interaction with platelet Gp IB:role of the heparin binding domain[J].Thrombosis and haemostasis,1997,77(4):735-740.
[25]BOYLE A J,RODDICK L A,BHAKTA V,et al.The complete N-terminal extension of heparin cofactor II is required for maximal effectiveness as a thrombin exosite 1ligand[J].BMC Biochem,2013(14):6.
[26]GAGAOUA M,HAFID K,BOUDIDA Y,et al.Caspases and Thrombin Activity Regulation by Specific Serpin Inhibitors in Bovine Skeletal Muscle[J].Appl Biochem Biotechnol,2015,177(2):279-303.
[27]KOUSTED T M,SKJOEDT K,PETERSEN S V,et al.Three monoclonal antibodies against the serpin protease nexin-1 prevent protease translocation[J].Thromb Haemost,2014,111(1):29-40.
[28]LIU Z,YU Z,HUANG Y,et al.A novel stearic acid-modified hirudin peptidomimetic with improved pharmacokinetic properties and anticoagulant activity[J].Sci Rep,2015(5):14349.
[29]KENNEDY B,GARGOUM F S,KENNEDY L,et al.Emerging anticoagulants[J].Curr Med Chem,2012,19(20):3388-3416.
[30]VORA A.Dabigatran etexilate in atrial fibrillation[J].J Assoc Physicians India,2013,61(12):900-902.
[31]DAS A,LIU D.Novel antidotes for target specific oral anticoagulants[J].Exp Hematol Oncol,2015(4):25.
[32]GLUND S,STANGIER J,SCHMOHL M,et al.Safety,tolerability,and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers:a randomised,placebo-controlled,double-blind phase 1 trial[J].Lancet,2015,386(9994):680-690.
[33]ERIKSSON B I,QUINLAN D J,WEITZ J I.Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor xa inhibitors in development[J].Clin Pharmacokinet,2009,48(1):1-22.
[34]ANDERSSON S,HOFMANN Y,NORDLING A,et al.Characterization and partial purification of the rat and human enzyme systems active in the reduction of Nhydroxymelagatran and benzamidoxime[J].Drug metabolism and disposition:the biological fate of chemicals,2005,33(4):570-578.
[35]JOHANSSON S,CULLBERG M,ERIKSSON U G,et al.Single-dose pharmacokinetics,pharmacodynamics and safety of AZD0837,a novel oral direct thrombin inhibitor,in young healthy male subjects[J].Int J Clin Pharmacol Ther,2011,49(4):258-267.
[36]GRESELE P,MOMI S.Inhibitors of the interaction between von Willebrand factor and platelet GPIb/IX/V[J].Handb Exp Pharmacol,2012(210):287-309.
[37]LEI X,REHEMAN A,HOU Y,et al.Anfibatide,a novel GPIb complex antagonist,inhibits platelet adhesion and thrombus formation in vitro and in vivo in murine models of thrombosis[J].Thromb Haemost,2014,111(2):279-289.
[38]LI T T,FAN M L,HOU S X,et al.A novel snake venomderived GPIb antagonist,anfibatide,protects mice from acute experimental ischaemic stroke and reperfusion injury[J].British journal of pharmacology,2015,172(15):3904-3916.
[39]FONTAYNE A,MEIRING M,LAMPRECHT S,et al.The humanized anti-glycoprotein Ib monoclonal antibody h6B4-Fab is a potent and safe antithrombotic in a high shear arterial thrombosis model in baboons[J].Thromb Haemost,2008,100(4):670-677.
[40]HENNAN J K,SWILLO R E,MORGAN G A,et al.Pharmacologic inhibition of platelet v WF-GPIb alpha interaction prevents coronary artery thrombosis[J].Thromb Haemost,2006,95(3):469-475.