抗血小板活性肽及其作用机制研究进展
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摘要
血小板的激活、聚集是血栓形成过程中的关键因素。然而,现有抗血小板药物虽能有效缓解血栓形成,但仍存在诸多问题。大量研究发现,多种天然生物活性肽存在抗血小板激活、聚集等活性,且安全有效、来源广泛、副作用小。本文首先介绍了血小板激活的不同机制,再对近年发表的抗血小板活性肽的来源、抗血小板聚集的效果以及抗血小板的作用机制进行了综述,以期为抗血小板肽作为膳食补充剂用于功能食品提供参考。
Platelet activation and aggregation play an important role in the initiation and progression of thrombosis.Consequently,the anti-platelet therapy can be beneficial for the patients of coronary and cerebrovascular diseases.The anti-platelet drugs can effectively relieve the formation of thrombus,but there are still several problems,such as drug resistance,low response and complications.Many studies have shown that many bioactive peptides have significant anti-platelet activities which are from wide range of sources,safe and effective,with few side effects.This article firstly introduce the mechanism of platelet activation,then reviews the sources of anti-platelet peptides,peptide sequence,the effect of platelet aggregation that published in recent years,and probes into the mechanism of anti-platelet peptide,in order to provide reference for antiplatelet peptide as dietary supplement for functional food.
Platelet activation and aggregation play an important role in the initiation and progression of thrombosis.Consequently,the anti-platelet therapy can be beneficial for the patients of coronary and cerebrovascular diseases.The anti-platelet drugs can effectively relieve the formation of thrombus,but there are still several problems,such as drug resistance,low response and complications.Many studies have shown that many bioactive peptides have significant anti-platelet activities which are from wide range of sources,safe and effective,with few side effects.This article firstly introduce the mechanism of platelet activation,then reviews the sources of anti-platelet peptides,peptide sequence,the effect of platelet aggregation that published in recent years,and probes into the mechanism of anti-platelet peptide,in order to provide reference for antiplatelet peptide as dietary supplement for functional food.
引文
1 Chen WW,et al.China cardiovascular disease report 2017summary[J].Chin Circ J(中国循环杂志),2018,33(1):1-8.
2 Li W.Glacocalyxin A inhibits platelet activation and thrombus formation via GPVI pathway[D].Suzhou:Soochow university(苏州大学),2013:23-24.
3 Zhang Y.Spontaneous activation of P2Y12 receptor and the role of Gi and G12-13 pathways in platelet activation and thrombosis[D].Shanghai:Fudan University(复旦大学),2013:59-71.
4 Badimon L,et al.The thrombotic disease:progress in antiplatelet therapy[J].Rev Esp Cardiol,2008,61:501-513.
5 Cheng H.Effects of theafavin(TF-1)on collagen-induced platelet activation and thrombosis formation[D].Hangzhou:Zhejiang University(浙江大学),2016:99-100.
6 Zhong CS,et al.When the platelet is activated,its calcium content is reduced with the number of particles[J].J Chin Electr Microsc Soc(电子显微学报),1996,1:301-306.
7 Kim S,et al.P2Y12 receptor in platelet activation[J].Platelets,2011,22(1):54-58.
8 Lu YK.Study on increasing calcium ansorption effect with collagen peptide from skin of Walleye Pollock[D].Qingdao:Ocean University of China(中国海洋大学),2013:84-90.
9 Nakanishi MM,et al.PAR3 is a cofactor for PAR4 activation by thrombin[J].Nature,2000,404:609-613.
10 Yu RM,et al.Marine Science Bulletin[J].Mar Sci Bull(海洋通报),2004,3:87-93.
11 De Luca G.Glycoprotein IIb-IIIa inhibitors[J].Cardiovasc Drug Ther,2012,30:242-254.
12 Liu D.Roles and mechanisms of chemokine CCL2 in platelet functions[D].Chongqing:Third Military Medical University(第三军医大学),2015:45-46.
13 Wan W,et al.Research progress of platelet associated active peptides[J].Clin Med(临床医学),2017,37:121-124.
14 Ruoslahti E,et al.Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule[J].Nature,1984,309(5963):30-33.
15 Xia MY,et al.Antiplatelet and antithrombotic activities of piper plants[J].Nat Prod Res Dev(天然产物研究与开发),2016,28:1676-1685.
16 Qian ZY,et al.Isolation and characterization of sheep lactoferrin,an inhibitor of platelet aggregation and comparison with human lactoferrin[J].Biochimica et Biophysica Acta,1995,1243(1):25-32.
17 Meddeb S,et al.A conformational study of Lys-Arg-Asp-Ser and analogs,a series of potent antithrombotic peptides.an approach based on simulated annealing and H NMR[J].J Biomol Struct Dyn,1994,11:959-981.
18 Jolles P,et al.Effect of an undecapeptide isolated from kappa-casein on platelet function[J].Eur J Bio,1986,158:379-382.
19 Khiari Z,et al.Structure elucidation of ACE-inhibitory and antithrombotic peptides isolated from mackerel skin gelatine hydrolysates[J].J Sci Food Agr,2014.94:1663-1671.
20 Maruyama S,et al.Inhibitory effects of enzymatic hydrolysates of collagen and collagen-related synthetic peptides on fibrinogen-thrombin clotting[J].Biochimica et Biophysica Acta 1993,1164:215-218.
21 Nonaka I,et al.In vitro and in vivo anti-platelet effects of enzymatic hydrolysates of collagen and collagen-related peptides[J].Biosci Biotech Bioch,1997,61:772-725.
22 Kong Y,et al.Purification and characterization of a novel antithrombotic peptide from Scolopendra subspinipes mutilans[J].J Ethnopharmacol,2013,145:182-186.
23 Hao X,et al.A novel ranacyclin-like peptide with anti-platelet activity identified from skin secretions of the frog Amolops loloensis[J].Gene,2016,576:171-175.
24 Kato H,et al.Ayadualin,a novel RGD peptide with dual antihemostatic activities from the sand fly Lutzomyia ayacuchensis,a vector of Andean-type cutaneous leishmaniasis[J].Biochimie,2015,112:49-56.
25 Chen M,et al.A novel direct factor Xa inhibitory peptide with anti-platelet aggregation activity from agkistrodon acutus venom hydrolysates[J].Sci Rep-uk,2015,5:10846.
26 Gan Z,et al.Echistatin,A potent platelet aggregation inhibitor fromthe venom of the viper[J].J Bio Chem,1988,36:19827-19832.
27 Huang S,et al.Trigramin.A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors[J].JBio Chem,1987,33:16157-16163.
28 Huang TF,et al.Halysin,an antiplatelet Arg-Gly-Asp-containing snake venom peptide,as fibrinogen receptor antagonist[J].Biochem Pharmacol,1991,42:1209-1219.
29 Huang TF,et al.An antiplatelet peptide,gabonin,from Bitis gabonica snake venom[J].Arch Biochem Biophys,1992,298(1):13-20.
30 Chanda C,et al.Novel thrombolytic protein from Cobra venom with anti-adhesive properties[J].Arch Biochem Biophys,2016,590:20-26.
31 Huang TF,et al.Mechanism of action of a potent antiplatelet peptide,triflavin from Trimeresurus flavoviridis snake venom[J].Thromb Haemostasis,1991,66:489.
32 Chen Z,et al.A novel platelet glycoprotein Ib-binding protein with human platelet aggregation-inhibiting activity from Trimeresurus jerdonii venom[J].Toxicon,2011,57:672-679.
33 Yeh CH,et al.A new short chain RGD-containing disintegrin,accutin,inhibits the common pathway of human platelet aggregation[J].Biochimica et Biophysica Acta-molecular Cell Res,1998,1425:493-504.
34 Liu Y,et al.Stimulation of nitric oxide production contributes to the antiplatelet and antithrombotic effect of new peptide p ENW(p Glu-Asn-Trp)[J].Thrombo Res,2015,136:319-327.
35 Andrieux A,et al.Amino acid sequences in fibrinogen mediating its interaction with its platelet receptor,GPIIb IIIa[J].JBio Chem,1989,264:9258-9265.
36 Yi K,et al.LX0702,a novel snake venom peptide derivative,inhibits thrombus formation via affecting the binding of fibrinogen with GPIIb-IIIa[J].J Pharmacol Sci.2015,127:462-466.
37 Hyun KW,et al.Isolation and characterization of a novel platelet aggregation inhibitory peptide from the medicinal mushroom,Inonotus obliquus[J].Peptides,2006,27:1173-1178.
38 Lee K,et al.SSGE and DEE,new peptides isolated from a soy protein hydrolysate that inhibit platelet aggregation[J].Food Chem,2005,90:389-393.
39 Tian MH,et al.Food and fermentation industries[J].Food Fermen Indus(食品与发酵工业),2014,06:110-116.
40 Yu,GY,et al.In vitro inhibition of platelet aggregation by peptides derived from oat(Avena sativa L.),highland barley(Hordeum vulgare Linn.var.nudum Hook.f.),and buckwheat(Fagopyrum esculentum Moench)proteins[J].Food Chem,2016,194:577-586.
41 Pytela R,et al.Platelet membrane glycoprotein IIb-IIIa:member of a family of Arg-Gly-Asp--specific adhesion receptors[J].Science,1986,231:1559-1562.
42 Martin M,et al.Novel antiplatelet drug revacept(Dimeric glycoprotein VI-Fc)specifically and efficiently inhibited1[J].J Am Heart Assoc,2011,123:1891-1899.
43 Aoki T,et al.The anti-platelet and anti-thrombotic effects of FK633,a peptide-mimetic GPIIB-IIIA antagonist[J].Throm Res,1996,81:439-450.
44 Connolly TM,et al.Species variability in platelet and other cellular responsiveness to thrombin receptor-derived peptides[J].Thromb Haemostasis,1994,72:627-633.
45 Roussa VD,et al.A highly constrained cyclic(S,S)-CDC-peptide is a potent inhibitor of carotid artery thrombosis in rabbits[J].Platelets,2011,22:361-370.
46 Barker PL,et al.Cyclic RGD peptide analogues as antiplatelet antithrombotics[J].J Med Chem,1992,35:2040-2048.
47 Morten LF,et al.Conformation-dependent platelet adhesion to collagen involving integrin alpha 2 beta 1-mediated and other mechanisms:multiple alpha 2 beta 1-recognition sites in collagen type I[J].J Biochem,1994,299:791-797.
48 Bruce EV,et al.A novel integrin specificity exemplified by binding of theαvβ5integrin to the basic domain of the HIVtat protein and vitronectin[J].J Cell Bio,1993,2:461-468.
49 Wang XX,et al.Studies about Ao GDW’s antiplatelet action in vitro[J].Chin Reme Clinics(中国药理学通报),2007,23:626-629.
50 Wen SM,et al.Systhesis of Nα-Ac-Arg-Gly-AspNHCH2CH2C6H5as an antiaggregatory agent[J].J General Hospital Air Force(空军总医院学报),1994,10:125-127.
51 Zhao HX,et al.RWR affects thrombosis by interaction with integrinαⅡbβ3receptor on surface of platelet[J].Chin J Bio(中国生物制品学杂志),2013,26:1126-1133.
52 Wu G,et al.Inhibition effects of KRDS,a peptide derived from lactotransferrin,on platelet function and arterial thrombus formation in dogs[J].Haemostasis,1992,22(1):1-6.
53 Li YB,et al.Antithrombotic effects and the conformation determination of KRDS,a synthetic peptide[J].Zoo Res(动物学研究),1994,14(S):106-113.
54 Xiong J,et al.New peptide p ENW(p Glu-Asn-Trp)inhibits platelet activation by attenuating Akt phosphorylation[J].Eur J Pharm Sci,2012,45:552-558.
55 Wang XH,et al.Study on platelet aggregation and ERK1-2phosphorylation by a non-arginyl-glycyl-aspartate peptide[J].Chi J Clin Lab Sci(临床检验杂志),2010,28:444-446.
56 Wang JC,et al.In vitro effects of a peptide mimetic(AC-RG-DPE)as an antiplatelet agent[J].Biorheology,1995,32:227.
57 Baker PL,et al.Cyclic RGD peptide analogues as antiplatelet antithrombotics[J].J Med Chem,1992,35:2040-2048.
58 Sarigianni YM,et al.Novel synthetic RGD analogs incorporating salicylic acid derivatives show antiplatelet activity in vitro[J].Let Peptide Sci,2002,9:101-109.
59 Wang JCh,et al.Effect of Nα-acetyl-arginyl-glycyl-aspartylp-methoxyl phenylethylamine on platelet aggregation[J].Chin J Pharm Toxi(中国药理学与毒理学杂志),2000,3:207-210.
60 Rydel TJ,et al.The structure of a complex of recombinant hirudin and human alpha-thrombin[J].Science,1990,249:277-280.
61 Huang YN.Structure basis of RGD-hirudin and development of new direct thrombin inhibitors[D].Shanghai:Fudan University(复旦大学),2013:97.
62 Wu G,et al.Novel peptide targeting integrin alphavbeta3-rich tumor cells by magnetic resonance imaging[J].J Magn Reson Imaging,2011,34:395-402.
63 Steg PG,et al.Bivalirudin started during emergency transport for primary PCI[J].New England J Med,2013,369:2207-2217.
64 Liu X,et al.A novel selective inhibitor to thrombin-induced platelet aggregation purified from the leech Whitmania pigra[J].Biochem Bioph Res Co,2016,473:349-354.
65 Sousa HR,et al.Novel antiplatelet role for a protein disulfide isomerase-targeted peptide:evidence of covalent binding to the C-terminal CGHC redox motif[J].J Thromb Haemost,2017,15:774-784.
2 Li W.Glacocalyxin A inhibits platelet activation and thrombus formation via GPVI pathway[D].Suzhou:Soochow university(苏州大学),2013:23-24.
3 Zhang Y.Spontaneous activation of P2Y12 receptor and the role of Gi and G12-13 pathways in platelet activation and thrombosis[D].Shanghai:Fudan University(复旦大学),2013:59-71.
4 Badimon L,et al.The thrombotic disease:progress in antiplatelet therapy[J].Rev Esp Cardiol,2008,61:501-513.
5 Cheng H.Effects of theafavin(TF-1)on collagen-induced platelet activation and thrombosis formation[D].Hangzhou:Zhejiang University(浙江大学),2016:99-100.
6 Zhong CS,et al.When the platelet is activated,its calcium content is reduced with the number of particles[J].J Chin Electr Microsc Soc(电子显微学报),1996,1:301-306.
7 Kim S,et al.P2Y12 receptor in platelet activation[J].Platelets,2011,22(1):54-58.
8 Lu YK.Study on increasing calcium ansorption effect with collagen peptide from skin of Walleye Pollock[D].Qingdao:Ocean University of China(中国海洋大学),2013:84-90.
9 Nakanishi MM,et al.PAR3 is a cofactor for PAR4 activation by thrombin[J].Nature,2000,404:609-613.
10 Yu RM,et al.Marine Science Bulletin[J].Mar Sci Bull(海洋通报),2004,3:87-93.
11 De Luca G.Glycoprotein IIb-IIIa inhibitors[J].Cardiovasc Drug Ther,2012,30:242-254.
12 Liu D.Roles and mechanisms of chemokine CCL2 in platelet functions[D].Chongqing:Third Military Medical University(第三军医大学),2015:45-46.
13 Wan W,et al.Research progress of platelet associated active peptides[J].Clin Med(临床医学),2017,37:121-124.
14 Ruoslahti E,et al.Cell attachment activity of fibronectin can be duplicated by small synthetic fragments of the molecule[J].Nature,1984,309(5963):30-33.
15 Xia MY,et al.Antiplatelet and antithrombotic activities of piper plants[J].Nat Prod Res Dev(天然产物研究与开发),2016,28:1676-1685.
16 Qian ZY,et al.Isolation and characterization of sheep lactoferrin,an inhibitor of platelet aggregation and comparison with human lactoferrin[J].Biochimica et Biophysica Acta,1995,1243(1):25-32.
17 Meddeb S,et al.A conformational study of Lys-Arg-Asp-Ser and analogs,a series of potent antithrombotic peptides.an approach based on simulated annealing and H NMR[J].J Biomol Struct Dyn,1994,11:959-981.
18 Jolles P,et al.Effect of an undecapeptide isolated from kappa-casein on platelet function[J].Eur J Bio,1986,158:379-382.
19 Khiari Z,et al.Structure elucidation of ACE-inhibitory and antithrombotic peptides isolated from mackerel skin gelatine hydrolysates[J].J Sci Food Agr,2014.94:1663-1671.
20 Maruyama S,et al.Inhibitory effects of enzymatic hydrolysates of collagen and collagen-related synthetic peptides on fibrinogen-thrombin clotting[J].Biochimica et Biophysica Acta 1993,1164:215-218.
21 Nonaka I,et al.In vitro and in vivo anti-platelet effects of enzymatic hydrolysates of collagen and collagen-related peptides[J].Biosci Biotech Bioch,1997,61:772-725.
22 Kong Y,et al.Purification and characterization of a novel antithrombotic peptide from Scolopendra subspinipes mutilans[J].J Ethnopharmacol,2013,145:182-186.
23 Hao X,et al.A novel ranacyclin-like peptide with anti-platelet activity identified from skin secretions of the frog Amolops loloensis[J].Gene,2016,576:171-175.
24 Kato H,et al.Ayadualin,a novel RGD peptide with dual antihemostatic activities from the sand fly Lutzomyia ayacuchensis,a vector of Andean-type cutaneous leishmaniasis[J].Biochimie,2015,112:49-56.
25 Chen M,et al.A novel direct factor Xa inhibitory peptide with anti-platelet aggregation activity from agkistrodon acutus venom hydrolysates[J].Sci Rep-uk,2015,5:10846.
26 Gan Z,et al.Echistatin,A potent platelet aggregation inhibitor fromthe venom of the viper[J].J Bio Chem,1988,36:19827-19832.
27 Huang S,et al.Trigramin.A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors[J].JBio Chem,1987,33:16157-16163.
28 Huang TF,et al.Halysin,an antiplatelet Arg-Gly-Asp-containing snake venom peptide,as fibrinogen receptor antagonist[J].Biochem Pharmacol,1991,42:1209-1219.
29 Huang TF,et al.An antiplatelet peptide,gabonin,from Bitis gabonica snake venom[J].Arch Biochem Biophys,1992,298(1):13-20.
30 Chanda C,et al.Novel thrombolytic protein from Cobra venom with anti-adhesive properties[J].Arch Biochem Biophys,2016,590:20-26.
31 Huang TF,et al.Mechanism of action of a potent antiplatelet peptide,triflavin from Trimeresurus flavoviridis snake venom[J].Thromb Haemostasis,1991,66:489.
32 Chen Z,et al.A novel platelet glycoprotein Ib-binding protein with human platelet aggregation-inhibiting activity from Trimeresurus jerdonii venom[J].Toxicon,2011,57:672-679.
33 Yeh CH,et al.A new short chain RGD-containing disintegrin,accutin,inhibits the common pathway of human platelet aggregation[J].Biochimica et Biophysica Acta-molecular Cell Res,1998,1425:493-504.
34 Liu Y,et al.Stimulation of nitric oxide production contributes to the antiplatelet and antithrombotic effect of new peptide p ENW(p Glu-Asn-Trp)[J].Thrombo Res,2015,136:319-327.
35 Andrieux A,et al.Amino acid sequences in fibrinogen mediating its interaction with its platelet receptor,GPIIb IIIa[J].JBio Chem,1989,264:9258-9265.
36 Yi K,et al.LX0702,a novel snake venom peptide derivative,inhibits thrombus formation via affecting the binding of fibrinogen with GPIIb-IIIa[J].J Pharmacol Sci.2015,127:462-466.
37 Hyun KW,et al.Isolation and characterization of a novel platelet aggregation inhibitory peptide from the medicinal mushroom,Inonotus obliquus[J].Peptides,2006,27:1173-1178.
38 Lee K,et al.SSGE and DEE,new peptides isolated from a soy protein hydrolysate that inhibit platelet aggregation[J].Food Chem,2005,90:389-393.
39 Tian MH,et al.Food and fermentation industries[J].Food Fermen Indus(食品与发酵工业),2014,06:110-116.
40 Yu,GY,et al.In vitro inhibition of platelet aggregation by peptides derived from oat(Avena sativa L.),highland barley(Hordeum vulgare Linn.var.nudum Hook.f.),and buckwheat(Fagopyrum esculentum Moench)proteins[J].Food Chem,2016,194:577-586.
41 Pytela R,et al.Platelet membrane glycoprotein IIb-IIIa:member of a family of Arg-Gly-Asp--specific adhesion receptors[J].Science,1986,231:1559-1562.
42 Martin M,et al.Novel antiplatelet drug revacept(Dimeric glycoprotein VI-Fc)specifically and efficiently inhibited1[J].J Am Heart Assoc,2011,123:1891-1899.
43 Aoki T,et al.The anti-platelet and anti-thrombotic effects of FK633,a peptide-mimetic GPIIB-IIIA antagonist[J].Throm Res,1996,81:439-450.
44 Connolly TM,et al.Species variability in platelet and other cellular responsiveness to thrombin receptor-derived peptides[J].Thromb Haemostasis,1994,72:627-633.
45 Roussa VD,et al.A highly constrained cyclic(S,S)-CDC-peptide is a potent inhibitor of carotid artery thrombosis in rabbits[J].Platelets,2011,22:361-370.
46 Barker PL,et al.Cyclic RGD peptide analogues as antiplatelet antithrombotics[J].J Med Chem,1992,35:2040-2048.
47 Morten LF,et al.Conformation-dependent platelet adhesion to collagen involving integrin alpha 2 beta 1-mediated and other mechanisms:multiple alpha 2 beta 1-recognition sites in collagen type I[J].J Biochem,1994,299:791-797.
48 Bruce EV,et al.A novel integrin specificity exemplified by binding of theαvβ5integrin to the basic domain of the HIVtat protein and vitronectin[J].J Cell Bio,1993,2:461-468.
49 Wang XX,et al.Studies about Ao GDW’s antiplatelet action in vitro[J].Chin Reme Clinics(中国药理学通报),2007,23:626-629.
50 Wen SM,et al.Systhesis of Nα-Ac-Arg-Gly-AspNHCH2CH2C6H5as an antiaggregatory agent[J].J General Hospital Air Force(空军总医院学报),1994,10:125-127.
51 Zhao HX,et al.RWR affects thrombosis by interaction with integrinαⅡbβ3receptor on surface of platelet[J].Chin J Bio(中国生物制品学杂志),2013,26:1126-1133.
52 Wu G,et al.Inhibition effects of KRDS,a peptide derived from lactotransferrin,on platelet function and arterial thrombus formation in dogs[J].Haemostasis,1992,22(1):1-6.
53 Li YB,et al.Antithrombotic effects and the conformation determination of KRDS,a synthetic peptide[J].Zoo Res(动物学研究),1994,14(S):106-113.
54 Xiong J,et al.New peptide p ENW(p Glu-Asn-Trp)inhibits platelet activation by attenuating Akt phosphorylation[J].Eur J Pharm Sci,2012,45:552-558.
55 Wang XH,et al.Study on platelet aggregation and ERK1-2phosphorylation by a non-arginyl-glycyl-aspartate peptide[J].Chi J Clin Lab Sci(临床检验杂志),2010,28:444-446.
56 Wang JC,et al.In vitro effects of a peptide mimetic(AC-RG-DPE)as an antiplatelet agent[J].Biorheology,1995,32:227.
57 Baker PL,et al.Cyclic RGD peptide analogues as antiplatelet antithrombotics[J].J Med Chem,1992,35:2040-2048.
58 Sarigianni YM,et al.Novel synthetic RGD analogs incorporating salicylic acid derivatives show antiplatelet activity in vitro[J].Let Peptide Sci,2002,9:101-109.
59 Wang JCh,et al.Effect of Nα-acetyl-arginyl-glycyl-aspartylp-methoxyl phenylethylamine on platelet aggregation[J].Chin J Pharm Toxi(中国药理学与毒理学杂志),2000,3:207-210.
60 Rydel TJ,et al.The structure of a complex of recombinant hirudin and human alpha-thrombin[J].Science,1990,249:277-280.
61 Huang YN.Structure basis of RGD-hirudin and development of new direct thrombin inhibitors[D].Shanghai:Fudan University(复旦大学),2013:97.
62 Wu G,et al.Novel peptide targeting integrin alphavbeta3-rich tumor cells by magnetic resonance imaging[J].J Magn Reson Imaging,2011,34:395-402.
63 Steg PG,et al.Bivalirudin started during emergency transport for primary PCI[J].New England J Med,2013,369:2207-2217.
64 Liu X,et al.A novel selective inhibitor to thrombin-induced platelet aggregation purified from the leech Whitmania pigra[J].Biochem Bioph Res Co,2016,473:349-354.
65 Sousa HR,et al.Novel antiplatelet role for a protein disulfide isomerase-targeted peptide:evidence of covalent binding to the C-terminal CGHC redox motif[J].J Thromb Haemost,2017,15:774-784.