The Discovery of Disintegrins

  • Tur-Fu HuangEmail author


Disintegrins represent a class of low molecular weight, Arg-Gly-Asp(RGD)/Lys-Gly-Asp(KGD)-containing, cysteine-rich polypeptides derived from venoms of various viper snakes. They bind to various integrins (e.g. αIIbβ3, αvβ3, α5β1 and others) expressed on cell membrane surface, with various degrees of affinity and specificity. Disintegrins were originally discovered as antiplatelet agents by acting as platelet membrane αIIbβ3 antagonists. However, they also have been found to bind αvβ3, α5β1 or α4β1 expressed on endothelial cells, fibroblasts, phagocytes, and tumor cells, thus affecting cell-matrix and cell-cell interaction. The homologous molecular structure among disintegrin, snake venom metalloproteinase (SVMP), and ADAM (a disintegrin and metalloproteinase) reveals their evolutionary relationship. Based on the structure-activity relationship of these molecules and integrins, the potential applications of these disintegrins and their derivatives are briefly discussed in field of arterial thrombosis, cell adhesion, cell migration, angiogenesis, inflammation, and tumor metastasis.


Platelet Aggregation Snake Venom Inhibit Platelet Aggregation Platelet Membrane Glycoprotein Experimental Metastasis Model 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



I would like to thank my Ph.D. thesis advisor, Dr. C. Ouyang, who encouraged me to stick on the topic entitled “Platelet inhibitory components in Trimeresurus gramineus venom” from which the first disintegrin Trigramin was discovered. Next, I also thank my partners Drs. S. Niewiarowski and Dr. J.C. Holt, Thrombosis Research Center, Temple University School of Medicine, who helped me to elucidate the primary sequence of the first naturally-occurring RGD-containing disintegrin, its primary target of platelet αIIbβ3,and its in vivo antithrombotic activity. Thanks to my graduate students and assistants for the devoted pursuit of the mysterious biology of snake venom. Finally, I appreciate the long-term financial support from National Science Council of Taiwan.


  1. Adler, M., Lazarus, R.A., Dennis, M.S., Wagner, G.., 1991. Solution structure of kistrin, a potent platelet aggregation inhibitor and GPIIb/IIIa antagonist. Science 253, 445–448.PubMedCrossRefGoogle Scholar
  2. Au, L.C., Chou, J.S., Chang, K.J., Teh, G.W., Lin, S.B., 1993. Nucleotide sequence of a full-length cDNA encoding a common precursor of platelet aggregation inhibitor and hemorrhagic protein from Calloselasma rhodostoma venom. Biochim. Biophys. Acta 1173, 243–245.PubMedCrossRefGoogle Scholar
  3. Au, L.C., Huang, Y.B., Huang, T.F., The, G.W., Lin, H.H., Choo, K.B., 1991. A common precursor for a putative hemorrhagic protein and rhodostomin, a platelet aggregation inhibitor of the venom of Calloselasma rhodostoma: molecular cloning and sequence analysis. Biochem. Biophys. Res. Commun. 181, 585–593.PubMedCrossRefGoogle Scholar
  4. Beer, J.H., Springer, K.T., Coller, B.S., 1992. Immobilized Arg-Gly-Asp (RGD) peptides of varying lengths as structural probes of the platelet glycoprotein IIb/IIIa receptor. Blood 79, 117–128.PubMedGoogle Scholar
  5. Brooks, P.C., Clark, R.A.F., Cheresh, D.A., 1994a. Requirement of vascular integrin alpha-v/beta-3 for angiogenesis. Science 264, 569–571.PubMedCrossRefGoogle Scholar
  6. Brooks, P.C., Montgomery, A.M., Rosenfeld, M., Reisfeld, R.A., Hu, T., Klier, G., 1994b. Integrin alpha-v/beta-3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels. Cell 79, 1157–1164.PubMedCrossRefGoogle Scholar
  7. Beviglia, L., Stewart, G.J., Niewiarowski, S., 1995. Effect of four disintegrins on the adhesive and metastatic properties of B16F10 melanoma cells in a murine model. Oncol. Res. 7, 7–20.PubMedGoogle Scholar
  8. Calvete, J.J., Moreno-Murciano, M.P., Theakston, R.D., Kisiel, D.G., Marcinkiewicz, C., 2003. Snake venom disintegrins: novel dimeric disintegrins and structural diversification by disulphide bond engineering. Biochem. J. 372, 725–734.PubMedCrossRefGoogle Scholar
  9. Chang, M.C., Jeng, J.H., Cheong, T.C., Huang, T.F., 1995b. The morphologic change of endothelial cells by ancrod-generated fibrin is triggered by alpha v beta 3 integrin binding and the subsequent activation of a G-protein coupled phospholipase C. Biochim. Biophys. Acta 1269, 115–121.PubMedCrossRefGoogle Scholar
  10. Chang, M.C., Wang, B.R., Huang, T.F., 1995a. Characterization of endothelial cell differential attachment to fibrin and fibrinogen and its inhibition by Arg-Gly-Asp-containing peptides. Thromb. Haemost. 74, 764–769.PubMedGoogle Scholar
  11. Chiang, H.S., Peng, H.C., Huang, T.F., 1994a. Characterization of integrin expression and regulation on SW-480 human colon adenocarcinoma cells and the effect of rhodostomin on basal and upregulated tumor cell adhesion. Biochim. Biophys. Acta 1224, 506–516.PubMedCrossRefGoogle Scholar
  12. Chiang, H.S., Swain, M.W., Huang, T.F., 1994b. Characterization of platelet aggregation induced by human colon adenocarcinoma cells and its inhibition by snake venom peptides, trigramin and rhodostomin. Br. J. Haematol. 87, 325–331.PubMedCrossRefGoogle Scholar
  13. Chiang, H.S., Yang, R.S., Huang, T.F., 1996. Thrombin enhances the adhesion and migration of human colon adenocarcinoma cells via increased beta 3-integrin expression on the tumour cell surface and their inhibition by the snake venom peptide, rhodostomin. Br. J. Cancer 73, 902–908.PubMedCrossRefGoogle Scholar
  14. Coller, B.S., 1990. Platelets and thrombolytic therapy. N. Engl. J. Med., 322, 33–42PubMedCrossRefGoogle Scholar
  15. Cook, J.J., Huang, T.F., Rucinski, B., Strzyzewski, M., Tuma, R.F., Williams, J.A., Niewiarowski, S., 1989. Inhibition of platelet hemostatic plug formation by trigramin, a novel RGD-peptide. Am. J. Physiol. 256, H1038–H1043.PubMedGoogle Scholar
  16. Fisher, J.E., Caulfield, M.P., Sato, M., Quartuccio, H.A., Gould, R.J., Garsky, V.M., Rodan, G.A., Rosenblatt, M., 1993. Inhibition of osteoclastic bone resorption in vivo by echistatin, an “arginyl-glycyl-aspartyl” (RGD)-containing protein. Endocrinology 132, 1411–1413.PubMedCrossRefGoogle Scholar
  17. Folkman, J., 1995. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat. Med. 1, 27–31PubMedCrossRefGoogle Scholar
  18. Folkman, J., Shing, Y., 1992. Angiogenesis. J. Biol. Chem. 267, 10931–10934PubMedGoogle Scholar
  19. Frank, J.D., Gould, R.J., Schaffer, L.W., Davidson, J.T., Gibson, R.E., Patrick, D.H., Vonderfecht, S.L., Cartwright, M.E., 1992. Immunocytochemical localization of platelets in baboon hepatic sinusoids using monoclonal mouse anti-human platelet glycoprotein IIIa following induction of thrombocytopenia. Histochemistry 97, 355–360.PubMedCrossRefGoogle Scholar
  20. Frelinger, A.L., Du, X.P., Plow, E.F., 1991. Monoclonal antibodies to ligand-occupied conformers of integrin alpha IIb beta 3 (glycoprotein IIb-IIIa) alter receptor affinity, specificity, and function. J. Biol. Chem. 266, 17106–17111.PubMedGoogle Scholar
  21. Fu, W.M., Chang, T.K., Sun, W.Z., Ling, Q.D., Peng, H.C., Liou, H.C., Lu, D.Y., Huang, T.F., 2004. Inhibition of neuropathic pain by a potent disintegrin – triflavin. Neurosci. Lett. 368, 263–268.PubMedCrossRefGoogle Scholar
  22. Gan, Z.R., Gould, R.J., Jacobs, J.W., Friedman, P.A., Polokoff, M.A., 1988. Echistatin: a potent platelet aggregation inhibitor from the venom of the viper, Echis carinatus. J. Biol. Chem. 263, 19827–19832.PubMedGoogle Scholar
  23. Gartner, T.K., Bennett, J.S., 1985. The tetrapeptide analogue of cell attachment site of fibrinogen inhibits platelet aggregation and fibrinogen binding to activated platelets. J. Biol. Chem. 269, 11891–11894.Google Scholar
  24. George, J.N., Caen, J.P., Nurden, A.T., 1990. Glanzmann’s thrombasthenia: the spectrum of clinical disease. Blood 75, 1383–1395.PubMedGoogle Scholar
  25. Ginsberg, M.H., Loftus, J.C., Plow, E.F., 1988. Cytoadhsion integrins and platelets. Thromb. Haemost. 59, 1–6.PubMedGoogle Scholar
  26. Gould, R.J., Polokoff, M.A., Friedman, P.A., Huang, T.F., Holt, J.C., Cook, J.J., Niewiarowski, S., 1990. Disintegrins: a family of integrin inhibitory proteins from viper venoms. Proc. Soc. Exp. Biol. Med. 195, 168–171.PubMedGoogle Scholar
  27. Hammes, H.P., Brownlee, M., Jonczyk, A., Sutter, A., Preissner, K.T., 1996. Subcutaneous injection of a cyclic peptide antagonist of vitronectin receptor-type integrins inhibits retinal neovascularization. Nat. Med. 2, 529–533.PubMedCrossRefGoogle Scholar
  28. Hite, L.A., Shannon, J.D., Bjarnason, J.B., Fox, J.W., 1992. Sequence of a cDNA clone encoding the zinc metalloproteinase hemorrhagic toxin e from Crotalus atrox: evidence for signal, zymogen, and disintegrin-like structures. Biochemistry 31, 6203–6211.PubMedCrossRefGoogle Scholar
  29. Hsu, C.C., Huang, T.F., 2009. A disintegrin, rhodostomin, inhibits activity of LPS-treated monocytes via αvβ3 integrin. J. Thromb. Haemost. 7, S2, Abstract PP-MO-879.CrossRefGoogle Scholar
  30. Huang, T.F., 1998. What have snakes taught us about integrins? Cell. Mol. Life Sci. 54, 527–540.PubMedCrossRefGoogle Scholar
  31. Huang, T.F., Holt, J.C., Kirby, E.P., Niewiarowski, S., 1989. Trigramin: primary structure and its inhibition of von Willebrand factor binding to glycoprotein IIb/IIIa complex on human platelets. Biochemistry 28, 661–666.PubMedCrossRefGoogle Scholar
  32. Huang, T.F., Holt, J.C., Lukasiewicz, H., Niewiarowski, S., 1987b. Trigramin. A low molecular weight peptide inhibiting fibrinogen interaction with platelet receptors expressed on glycoprotein IIb-IIIa complex. J. Biol. Chem. 262, 16157–16163.PubMedGoogle Scholar
  33. Huang, T.F., Liu, C.Z., Ouyang, C., Teng, C.M., 1991a. Halysin, an antiplatelet Arg-Gly-Asp-containing snake venom peptides, as fibrinogen receptor antagonist. Biochem. Pharmacol. 42, 1209–1219.PubMedCrossRefGoogle Scholar
  34. Huang, T.F., Ouyang, C., 1984. Action mechanism of the potent platelet aggregation inhibitor from Trimeresurus gramineus snake venom. Thromb. Res. 33, 125–138.PubMedCrossRefGoogle Scholar
  35. Huang, T.F., Sheu, J.R., Teng, C.M., Chen, S.W., Liu, C.S., 1991b. Triflavin, an antiplatelet Arg-Gly-Asp-containing peptide, is a specific antagonist of platelet membrane glycoprotein IIb-IIIa complex. J. Biochem. (Tokyo) 109, 328–334.Google Scholar
  36. Huang, T.F., Wang, W.J., Teng, C.M., Ouyang, C., 1991c. Mechanism of action of the antiplatelet peptide, arietin, from Bitis arietans venom. Biochim. Biophys. Acta. 1074, 144–150.PubMedCrossRefGoogle Scholar
  37. Huang, T.F., Wu, Y.J., Ouyang, C., 1987a. Characterization of a potent platelet aggregation inhibitor from Agkistrodon rhodostoma snake venom. Biochim. Biophys. Acta 925, 248–257.PubMedCrossRefGoogle Scholar
  38. Hynes, R.O., 1992. Integrins: versatility, modulation and signaling in cell adhesion. Cell 69, 11–25.PubMedCrossRefGoogle Scholar
  39. Jia, L.G., Wang, X.M., Shannon, J.D., Bjarnason, J.B., Fox, J.W., 1997. Function of disintegrin-like/cysteine-rich domains of atrolysin A. Inhibition of platelet aggregation by recombinant protein and peptide antagonists. J. Biol. Chem. 272, 13094–13102.PubMedCrossRefGoogle Scholar
  40. Jin, H., Varner, J., 2004. Integrins: roles in cancer development and as treatment targets. Br. J. Cancer 90, 561–565.PubMedCrossRefGoogle Scholar
  41. Kini, R.M., Evans, H.J., 1992. Structural domains in venom proteins: evidence that metalloproteinases and nonenzymatic platelet aggregation inhibitors (disintegrins) from snake venoms are derived by proteolysis from a common precursor. Toxicon 30, 265–293.PubMedCrossRefGoogle Scholar
  42. Knudsen, K.A., Tuszynski, G.P., Huang, T.F., Niewiarowski, S., 1988. Trigramin, an RGD-containing peptide from snake venom, inhibits cell-substratum adhesion of human melanoma cells. Exp. Cell Res. 179, 42–49.PubMedCrossRefGoogle Scholar
  43. Lin, Y.T., Tang, C.H., Chuang, W.J., Wang, S.M., Huang, T.F., Fu, W.M., 2005. Inhibition of adipogenesis by RGD-dependent disintegrin. Biochem. Pharmacol. 70, 1469–1478.PubMedCrossRefGoogle Scholar
  44. Liu, C.Z., Hur, B.T., Huang, T.F., 1996. Measurement of glycoprotein IIb/IIIa blockade by flow cytometry with fluoresein isothiocyanate-conjugated crotavirin, a member of disintegrins. Thromb. Haemostas. 76, 585–591.Google Scholar
  45. Liu, C.Z., Wang, Y.W., Shen, M.C., Huang, T.F., 1994. Analysis of human platelet glycoprotein IIb/IIIa by fluorescein isothiocyanate-conjugated disintegrins with flow cytometry. Thromb. Haemostas. 72, 919–925.Google Scholar
  46. Lu, Q., Clemetson, J.M., Clemetson, K.J., 2005. Snake venoms and hemostasis. J. Thromb. Haemost. 3, 1791–1799.PubMedCrossRefGoogle Scholar
  47. Marcinkiewicz, C., Calvete, J.J., Marcinkiewicz, M.M., Raida, M., Vijay-Kumar, S., Huang, Z., Lobb, R.R., Niewiarowski, S., 1999. EC3, a novel heterodimeric disintegrin from Echis carinatus venom, inhibits alpha4 and alpha5 integrins in an RGD-independent manner. J. Biol. Chem. 274, 12468–12473.PubMedCrossRefGoogle Scholar
  48. Menter, D.G., Steinert, B.W., Sloane, B.F., Gundlach, N., O’Gara, C.Y., Marnett, L.J., Diglio, C., Walz, D., Taylor, J.D., Honn, K.V., 1987. Role of platelet membrane in enhancement of tumor cell adhesion to endothelial cell extracellular matrix. Cancer Res. 47, 6751–6762.PubMedGoogle Scholar
  49. Mould, A.P., Symonds, E.J., Buckley, P.A., Grossmann, J.G., McEwan, P.A., Barton, S.J., Askari, J.A., Craig, S.E., Bella, J., Humphries, M.J., 2003. Structure of an integrin-ligand complex deduced from solution x-ray scattering and site-directed mutagenesis. J. Biol. Chem. 278, 39993–39999.PubMedCrossRefGoogle Scholar
  50. Musial, J., Niewiarowski, S., Rucinski, B., Stewart, G.J., Cook, J.J., Williams, J.A., Edmunds, L.H., Jr., 1990. Inhibition of platelet adhesion to surfaces of extracorporeal circuits by disintegrins. RGD-containing peptides from viper venoms. Circulation 82, 261–273.PubMedCrossRefGoogle Scholar
  51. Nieuwenhuis, H.K., Akkerman, J.W., Houdijk, W.P., Sixma, J.J., 1985. Human blood platelets showing no response to collagen fail to express surface glycoprotein Ia. Nature 318, 470–472.PubMedCrossRefGoogle Scholar
  52. Ouyang, C., Huang, T.F., 1983. Potent platelet aggregation inhibitor from Trimeresurus gramineus snake venom. Biochim. Biophys. Acta 757, 332–341.PubMedCrossRefGoogle Scholar
  53. Ouyang, C., Teng, C.M., Huang, T.F., 1992. Characterization of snake venom components acting on blood coagulation and platelet function. Toxicon 30, 945–966.PubMedCrossRefGoogle Scholar
  54. Ouyang, C., Yeh, H.I., Huang, T.F., 1983. A potent platelet aggregation inhibitor purified from Agkistrodon halys (mamushi) snake venom. Toxicon 21, 797–804.PubMedCrossRefGoogle Scholar
  55. Paine, M.J., Desmond, H.P., Theakston, R.D., Crampton, J.M., 1992. Purification, cloning, and molecular characterization of a high molecular weight hemorrhagic metalloprotease, jararhagin, from Bothrops jararaca venom. Insights into the disintegrin gene family. J. Biol. Chem. 267, 22869–22876.PubMedGoogle Scholar
  56. Rote, W.E., Mu, D.X., Roncinske, R.A., Frelinger, A.L., 3rd, Lucchesi, B.R., 1993. Prevention of experimental carotid artery thrombosis by applaggin. J. Pharmacol. Exp. Ther. 267, 809–814.PubMedGoogle Scholar
  57. Rucinski, B., Niewiarowski, S., Holt, J.C., Soszka, T., Knudsen, K.A., 1990. Batroxostatin, an Arg-Gly-Asp containing peptide from Bothrops atrox, a potent inhibitor of platelet aggregation and cell interaction with fibronectin. Biochem. Biophys. Acta 1054, 257–262.PubMedCrossRefGoogle Scholar
  58. Sato, M., Sardana, M.K., Grasser, W.A., Garsky, V.M., Murray, J.M., Gould, R.J., 1990. Echistatin is a potent inhibitor of bone resorption in culture. J. Cell Biol. 111, 1713–1723.PubMedCrossRefGoogle Scholar
  59. Savage, B., Marzec, U.M., Chao, B.H., Harker, L.A., Maragnone, J.M., Ruggeri, Z.M., 1990. Binding of the snake venom-derived proteins applagin and echistatin to the arginine-glycine-aspartic acid recognition site(s) on platelet glycoprotein IIb/IIIa complex inhibits receptor function. J. Biol. Chem. 265, 11766–11772.PubMedGoogle Scholar
  60. Scarborough, R.M., Naughton, M.A., Teng, W., Rose, J.W., Phillips, D.R., Nannizzi, L., Arfsten, A., Campbell, A.M., Charo, I.F., 1993a. Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa. J. Biol. Chem. 268, 1066–1073.PubMedGoogle Scholar
  61. Scarborough, R.M., Rose, J.W., Hsu, M.A., Phillips, D.R., Fried, V.A., Campbell, A.M. Nannizzi, L., Charo, I.F., 1991. Barbourin. A GPIIb-IIIa-specific integrin antagonists from the venom of Sistrurus m. barbouri. J. Biol. Chem. 266, 9359–9362.PubMedGoogle Scholar
  62. Scarborough, R.M., Rose, J.W., Naughton, M.A., Philips, D.R., Nannizzi, L., Arfsten, A., Campbell, A.M., Charo, I.F., 1993b. Characterization of the integrin specificities of disintegrins isolated from American pit viper venoms. J. Biol. Chem. 268, 1058–1065.PubMedGoogle Scholar
  63. Sheu, J.R., Lin, C.H., Chuang, J.L., Teng, C.M., Huang, T.F., 1992a. Triflavin, an Arg-Gly-Asp-containing snake venom peptide, inhibits aggregation of human platelets induced by human hepatoma cell line. Thromb. Res. 66, 679–691.PubMedCrossRefGoogle Scholar
  64. Sheu, J.R., Lin, C.H., Chung, J.L., Teng, C.M., Huang, T.F., 1992b. Triflavin, an Arg-Gly-Asp-containing antiplatelet peptide inhibits cell-substratum adhesion and melanoma cell-induced lung colonization. Jpn. J. Cancer Res. 83, 885–893.PubMedCrossRefGoogle Scholar
  65. Sheu, J.R., Lin, C.H., Huang, T.F., 1994a. Triflavin, an antiplatelet peptide inhibits tumor cell-extracellular matrix adhesion via an RGD-dependent mechanism. J. Lab. Clin. Med. 123, 256–263.PubMedGoogle Scholar
  66. Sheu, J.R., Lin, C.H., Peng, H.C., Huang, T.F., 1994b. Triflavin, an Arg-Gly-Asp-containing peptide, inhibits human cervical carcinoma (HeLa) cell-substratum adhesion through an RGD-dependent mechanism. Peptides 15, 1391–1398.PubMedCrossRefGoogle Scholar
  67. Sheu, J.R., Lin, C.H., Peng, H.C., Huang, T.F., 1996. Triflavin, an Arg-Gly-Asp-containing peptide, inhibits the adhesion of tumor cells to matrix proteins via binding to multiple integrin receptors expressed on human hepatoma cells. Proc. Soc. Exp. Biol. Med. 213, 71–79.PubMedGoogle Scholar
  68. Sheu, J.R., Teng, C.M., Huang, T.F., 1992c. Triflavin, an RGD-containing antiplatelet peptide, binds to GpIIIa of ADP-stimulated platelets. Biochem. Biophys. Res. Commun. 189, 1236–1342.PubMedCrossRefGoogle Scholar
  69. Sheu, J.R., Yen, M.H., Hung, W.C., Lee, Y.M., Su, C.H., Huang, T.F., 1997. Triflavin inhibits platelet-induced vasoconstriction in de-endothelialized aorta. Arterioscler. Thromb. Vasc. Biol. 17, 3461–3468.PubMedCrossRefGoogle Scholar
  70. Suehiro, K, Smith, J.W., Plow, E.F., 1996. The ligand recognition specificity of ß3 integrins. J. Biol. Chem. 271, 10365–10371PubMedCrossRefGoogle Scholar
  71. Swaim, M.W., Chiang, H.S., Huang, T.F., 1996. Characterisation of platelet aggregation induced by PC-3 human prostate adenocarcinoma cells and inhibited by venom peptides, trigramin and rhodostomin. Eur. J. Cancer 32A, 715–721.PubMedCrossRefGoogle Scholar
  72. Swenson, S., Ramu, S., Markland, F.S., 2007. Anti-angiogenesis and RGD-containing snake venom disintegrins. Curr. Pharm. Des. 13, 2860–3871.PubMedCrossRefGoogle Scholar
  73. Takeda, S., 2009. Three-dimensional domain architecture of the ADAM family proteinases. Semin. Cell Dev. Biol. 20, 146–152.PubMedCrossRefGoogle Scholar
  74. Takeya, H., Oda, K., Miyata, J., Omori-Satoh, T., Iwanaga, S., 1990. The complete amino acid sequence of high molecular mass haemorrhagic protein HR1B isolated from the venom Trimeresurus flavoviridis. J. Biol. Chem. 265, 16068–16073.PubMedGoogle Scholar
  75. Tcheng, J.E., Harrington, R.A., Kottke-Marchant, K., Kleiman, N.S., Ellis, S.G., Kereiakes, D.J., Mick, M.J., Navetta, F.I., Smith, J.E., Worley, S.J., Miller, J.A., Joseph, D.M., Sigmon, K.N., Kitt, M.M., du Mée, C.P., Califf, R.M., Topol, E.J., 1995. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker Integrelin in elective coronary intervention. IMPACT Investigators. Circulation 91, 2151–2157.CrossRefGoogle Scholar
  76. Teng, C.M., Huang, T.F., 1991. Snake venom constituents that affect platelet function. Platelets 2, 77–87.PubMedCrossRefGoogle Scholar
  77. The EPIC investigations. 1994. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N. Engl. J. Med. 330, 956–961.CrossRefGoogle Scholar
  78. Tsai, T.J., Sheu, J.R., Chen, Y.M., Yen, C.J., Chen, C.F., Huang, T.F., 1995. Disintegrin modulates rat glomerular mesangial cell behavior. Nephron 70, 83–90.PubMedCrossRefGoogle Scholar
  79. Tseng, Y.L., Peng, H.C., Huang, T.F., 2004. Rhodostomin, a disintegrin, inhibits adhesion of neutrophils to fibrinogen and attenuates superoxide production. J. Biomed. Sci. 11, 683–691.PubMedCrossRefGoogle Scholar
  80. Watson, S.P, Auger, J.M., McCarty, O.J., Pearce, A.C., 2005. GPVI and integrin alphaIIb beta3 signaling in platelets. J. Thromb. Haemost. 3, 1752–1762.PubMedCrossRefGoogle Scholar
  81. Weller, T., Alig, L., Muller, M.H., Kouns, W.C., Steiner, B., 1994. Fibrinogen receptor antagonists - a novel class of promising antithrombotics. Drugs Future 19, 461–476.Google Scholar
  82. Wesolowski, G., Duong, L.T., Lakkakorpi, P.T., Nagy, R.M., Tezuka, K., Tanaka, H., Rodan, G.A., Rodan, S.B., 1995. Isolation and characterization of highly enriched, prefusion mouse osteoclastic cells. Exp. Cell Res. 219, 679–686.PubMedCrossRefGoogle Scholar
  83. Wu, W.B., Peng, H.C., Huang, T.F., 2003. Disintegrin causes proteolysis of beta-catenin and apoptosis of endothelial cells. Involvement of cell-cell and cell-ECM interactions in regulating cell viability. Exp. Cell Res. 286, 115–127.PubMedCrossRefGoogle Scholar
  84. Yang, R.S., Tang, C.H., Chuang, W.J., Huang, T.H., Peng, H.C., Huang, T.F., Fu, W.M., 2005. Inhibition of tumor formation by snake venom disintegrin. Toxicon 45, 661–669.PubMedCrossRefGoogle Scholar
  85. Yasuda, T., Gold, H.K., Leinbach, R.C., Yaoita, H., Fallon, J.T., Guerrero, L., Napier, M.A., Bunting, S., Collen, D., 1991. Kistrin, a polypeptide platelet GPIIb/IIIa receptor antagonist, enhances and sustains coronary arterial thrombolysis with recombinant tissue-type plasminogen activator in a canine preparation. Circulation 83, 1038–1047.PubMedCrossRefGoogle Scholar
  86. Yeh, C.H., Peng, H.C., Huang, T.F., 1998. Accutin, a new disintegrin, inhibits angiogenesis in vitro and in vivo by acting as integrin alphavbeta3 antagonist and inducing apoptosis. Blood 92, 3268–3276.PubMedGoogle Scholar
  87. Yeh, C.H., Peng, H.C., Yang, R.S., Huang, T.F., 2001. Rhodostomin, a snake venom disintegrin, inhibits angiogenesis elicited by basic fibroblast growth factor and suppresses tumor growth by a selective αvβ3 blockade of endothelial cells. Mol. Pharmacol. 59, 1333–1342.PubMedGoogle Scholar

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© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  1. 1.Institute of Pharmacology, College of Medicine, National Taiwan UniversityTaipeiTaiwan

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