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. 1994 Aug 1;301(Pt 3):785–791. doi: 10.1042/bj3010785

Tetrafibricin, a novel non-peptide fibrinogen receptor antagonist, induces conformational changes in glycoprotein IIb/IIIa.

T Satoh 1, W C Kouns 1, Y Yamashita 1, T Kamiyama 1, B Steiner 1
PMCID: PMC1137056  PMID: 7519850

Abstract

Arg-Gly-Asp (RGD) is an amino acid sequence in fibrinogen recognized by platelet glycoprotein (GP) IIb/IIIa. Recently, it was found that RGD peptide binding to GPIIb/IIIa leads to conformational changes in the complex that are associated with the acquisition of high-affinity fibrinogen-binding function. In this study, we found that tetrafibricin, a novel non-peptidic GPIIb/IIIa antagonist, induced similar conformational changes in GPIIb/IIIa as did RGD peptides. Tetrafibricin increased the binding of purified inactive GPIIb/IIIa to immobilized pl-80, a monoclonal antibody that preferentially recognizes ligand-occupied GPIIb/IIIa. Exposure of the pl-80 epitope by tetrafibricin was also observed on resting human platelets by flow cytometry. On intact platelets, the conformational changes transformed GPIIb/IIIa into a high-affinity receptor for fibrinogen and triggered subsequent platelet aggregation. Tetrafibricin is the first non-peptidic GPIIb/IIIa antagonist reported that has the capacity to induce conformational changes in GPIIb/IIIa.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Andrieux A., Hudry-Clergeon G., Ryckewaert J. J., Chapel A., Ginsberg M. H., Plow E. F., Marguerie G. Amino acid sequences in fibrinogen mediating its interaction with its platelet receptor, GPIIbIIIa. J Biol Chem. 1989 Jun 5;264(16):9258–9265. [PubMed] [Google Scholar]
  2. Andrieux A., Rabiet M. J., Chapel A., Concord E., Marguerie G. A highly conserved sequence of the Arg-Gly-Asp-binding domain of the integrin beta 3 subunit is sensitive to stimulation. J Biol Chem. 1991 Aug 5;266(22):14202–14207. [PubMed] [Google Scholar]
  3. Bachelot C., Rendu F., Boucheix C., Hogg N., Levy-Toledano S. Activation of platelets induced by mAb P256 specific for glycoprotein IIb-IIIa. Possible evidence for a role for IIb-IIIa in membrane signal transduction. Eur J Biochem. 1990 May 31;190(1):177–183. doi: 10.1111/j.1432-1033.1990.tb15562.x. [DOI] [PubMed] [Google Scholar]
  4. Banga H. S., Simons E. R., Brass L. F., Rittenhouse S. E. Activation of phospholipases A and C in human platelets exposed to epinephrine: role of glycoproteins IIb/IIIa and dual role of epinephrine. Proc Natl Acad Sci U S A. 1986 Dec;83(23):9197–9201. doi: 10.1073/pnas.83.23.9197. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barker P. L., Bullens S., Bunting S., Burdick D. J., Chan K. S., Deisher T., Eigenbrot C., Gadek T. R., Gantzos R., Lipari M. T. Cyclic RGD peptide analogues as antiplatelet antithrombotics. J Med Chem. 1992 May 29;35(11):2040–2048. doi: 10.1021/jm00089a014. [DOI] [PubMed] [Google Scholar]
  6. Cabañas C., Hogg N. Ligand intercellular adhesion molecule 1 has a necessary role in activation of integrin lymphocyte function-associated molecule 1. Proc Natl Acad Sci U S A. 1993 Jun 15;90(12):5838–5842. doi: 10.1073/pnas.90.12.5838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Carteaux J. P., Roux S., Kuhn H., Tschopp T., Colombo V., Hadváry P. Ro 44-9883, a new nonpeptide glycoprotein IIb/IIIa antagonist, prevents platelet loss during experimental cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1993 Nov;106(5):834–841. [PubMed] [Google Scholar]
  8. D'Souza S. E., Ginsberg M. H., Burke T. A., Lam S. C., Plow E. F. Localization of an Arg-Gly-Asp recognition site within an integrin adhesion receptor. Science. 1988 Oct 7;242(4875):91–93. doi: 10.1126/science.3262922. [DOI] [PubMed] [Google Scholar]
  9. D'Souza S. E., Ginsberg M. H., Plow E. F. Arginyl-glycyl-aspartic acid (RGD): a cell adhesion motif. Trends Biochem Sci. 1991 Jul;16(7):246–250. doi: 10.1016/0968-0004(91)90096-e. [DOI] [PubMed] [Google Scholar]
  10. Dennis M. S., Henzel W. J., Pitti R. M., Lipari M. T., Napier M. A., Deisher T. A., Bunting S., Lazarus R. A. Platelet glycoprotein IIb-IIIa protein antagonists from snake venoms: evidence for a family of platelet-aggregation inhibitors. Proc Natl Acad Sci U S A. 1990 Apr;87(7):2471–2475. doi: 10.1073/pnas.87.7.2471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Du X. P., Plow E. F., Frelinger A. L., 3rd, O'Toole T. E., Loftus J. C., Ginsberg M. H. Ligands "activate" integrin alpha IIb beta 3 (platelet GPIIb-IIIa). Cell. 1991 May 3;65(3):409–416. doi: 10.1016/0092-8674(91)90458-b. [DOI] [PubMed] [Google Scholar]
  12. Fitzgerald L. A., Leung B., Phillips D. R. A method for purifying the platelet membrane glycoprotein IIb-IIIa complex. Anal Biochem. 1985 Nov 15;151(1):169–177. doi: 10.1016/0003-2697(85)90067-3. [DOI] [PubMed] [Google Scholar]
  13. Frelinger A. L., 3rd, Cohen I., Plow E. F., Smith M. A., Roberts J., Lam S. C., Ginsberg M. H. Selective inhibition of integrin function by antibodies specific for ligand-occupied receptor conformers. J Biol Chem. 1990 Apr 15;265(11):6346–6352. [PubMed] [Google Scholar]
  14. Ginsberg M. H., Forsyth J., Lightsey A., Chediak J., Plow E. F. Reduced surface expression and binding of fibronectin by thrombin-stimulated thrombasthenic platelets. J Clin Invest. 1983 Mar;71(3):619–624. doi: 10.1172/JCI110808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ginsberg M. H., Frelinger A. L., Lam S. C., Forsyth J., McMillan R., Plow E. F., Shattil S. J. Analysis of platelet aggregation disorders based on flow cytometric analysis of membrane glycoprotein IIb-IIIa with conformation-specific monoclonal antibodies. Blood. 1990 Nov 15;76(10):2017–2023. [PubMed] [Google Scholar]
  16. Häring P., Stähli C., Schoch P., Takács B., Staehelin T., Möhler H. Monoclonal antibodies reveal structural homogeneity of gamma-aminobutyric acid/benzodiazepine receptors in different brain areas. Proc Natl Acad Sci U S A. 1985 Jul;82(14):4837–4841. doi: 10.1073/pnas.82.14.4837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kamiyama T., Umino T., Fujisaki N., Fujimori K., Satoh T., Yamashita Y., Ohshima S., Watanabe J., Yokose K. Tetrafibricin, a novel fibrinogen receptor antagonist. I. Taxonomy, fermentation, isolation, characterization and biological activities. J Antibiot (Tokyo) 1993 Jul;46(7):1039–1046. doi: 10.7164/antibiotics.46.1039. [DOI] [PubMed] [Google Scholar]
  18. Kouns W. C., Hadvary P., Haering P., Steiner B. Conformational modulation of purified glycoprotein (GP) IIb-IIIa allows proteolytic generation of active fragments from either active or inactive GPIIb-IIIa. J Biol Chem. 1992 Sep 15;267(26):18844–18851. [PubMed] [Google Scholar]
  19. Kouns W. C., Jennings L. K. Activation-independent exposure of the GPIIb-IIIa fibrinogen receptor. Thromb Res. 1991 Aug 1;63(3):343–354. doi: 10.1016/0049-3848(91)90137-l. [DOI] [PubMed] [Google Scholar]
  20. Kouns W. C., Kirchhofer D., Hadváry P., Edenhofer A., Weller T., Pfenninger G., Baumgartner H. R., Jennings L. K., Steiner B. Reversible conformational changes induced in glycoprotein IIb-IIIa by a potent and selective peptidomimetic inhibitor. Blood. 1992 Nov 15;80(10):2539–2547. [PubMed] [Google Scholar]
  21. Kouns W. C., Wall C. D., White M. M., Fox C. F., Jennings L. K. A conformation-dependent epitope of human platelet glycoprotein IIIa. J Biol Chem. 1990 Nov 25;265(33):20594–20601. [PubMed] [Google Scholar]
  22. Lam S. C., Plow E. F., Smith M. A., Andrieux A., Ryckwaert J. J., Marguerie G., Ginsberg M. H. Evidence that arginyl-glycyl-aspartate peptides and fibrinogen gamma chain peptides share a common binding site on platelets. J Biol Chem. 1987 Jan 25;262(3):947–950. [PubMed] [Google Scholar]
  23. Marguerie G. A., Plow E. F., Edgington T. S. Human platelets possess an inducible and saturable receptor specific for fibrinogen. J Biol Chem. 1979 Jun 25;254(12):5357–5363. [PubMed] [Google Scholar]
  24. Mazoyer E., Lévy-Toledano S., Rendu F., Hermant L., Lu H., Fiat A. M., Jollès P., Caen J. KRDS, a new peptide derived from human lactotransferrin, inhibits platelet aggregation and release reaction. Eur J Biochem. 1990 Nov 26;194(1):43–49. doi: 10.1111/j.1432-1033.1990.tb19424.x. [DOI] [PubMed] [Google Scholar]
  25. Mickelson J. K., Simpson P. J., Cronin M., Homeister J. W., Laywell E., Kitzen J., Lucchesi B. R. Antiplatelet antibody [7E3 F(ab')2] prevents rethrombosis after recombinant tissue-type plasminogen activator-induced coronary artery thrombolysis in a canine model. Circulation. 1990 Feb;81(2):617–627. doi: 10.1161/01.cir.81.2.617. [DOI] [PubMed] [Google Scholar]
  26. Nichols A. J., Ruffolo R. R., Jr, Huffman W. F., Poste G., Samanen J. Development of GPIIb/IIIa antagonists as antithrombotic drugs. Trends Pharmacol Sci. 1992 Nov;13(11):413–417. doi: 10.1016/0165-6147(92)90126-q. [DOI] [PubMed] [Google Scholar]
  27. Nicholson N. S., Panzer-Knodle S. G., Salyers A. K., Taite B. B., King L. W., Miyano M., Gorczynski R. J., Williams M. H., Zupec M. E., Tjoeng F. S. In vitro and in vivo effects of a peptide mimetic (SC-47643) of RGD as an antiplatelet and antithrombotic agent. Thromb Res. 1991 Jun 1;62(5):567–578. doi: 10.1016/0049-3848(91)90029-v. [DOI] [PubMed] [Google Scholar]
  28. O'Toole T. E., Loftus J. C., Du X. P., Glass A. A., Ruggeri Z. M., Shattil S. J., Plow E. F., Ginsberg M. H. Affinity modulation of the alpha IIb beta 3 integrin (platelet GPIIb-IIIa) is an intrinsic property of the receptor. Cell Regul. 1990 Nov;1(12):883–893. doi: 10.1091/mbc.1.12.883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Parise L. V., Helgerson S. L., Steiner B., Nannizzi L., Phillips D. R. Synthetic peptides derived from fibrinogen and fibronectin change the conformation of purified platelet glycoprotein IIb-IIIa. J Biol Chem. 1987 Sep 15;262(26):12597–12602. [PubMed] [Google Scholar]
  30. Parise L. V., Phillips D. R. Reconstitution of the purified platelet fibrinogen receptor. Fibrinogen binding properties of the glycoprotein IIb-IIIa complex. J Biol Chem. 1985 Sep 5;260(19):10698–10707. [PubMed] [Google Scholar]
  31. Peerlinck K., De Lepeleire I., Goldberg M., Farrell D., Barrett J., Hand E., Panebianco D., Deckmyn H., Vermylen J., Arnout J. MK-383 (L-700,462), a selective nonpeptide platelet glycoprotein IIb/IIIa antagonist, is active in man. Circulation. 1993 Oct;88(4 Pt 1):1512–1517. doi: 10.1161/01.cir.88.4.1512. [DOI] [PubMed] [Google Scholar]
  32. Phillips D. R., Charo I. F., Scarborough R. M. GPIIb-IIIa: the responsive integrin. Cell. 1991 May 3;65(3):359–362. doi: 10.1016/0092-8674(91)90451-4. [DOI] [PubMed] [Google Scholar]
  33. Pytela R., Pierschbacher M. D., Ginsberg M. H., Plow E. F., Ruoslahti E. Platelet membrane glycoprotein IIb/IIIa: member of a family of Arg-Gly-Asp--specific adhesion receptors. Science. 1986 Mar 28;231(4745):1559–1562. doi: 10.1126/science.2420006. [DOI] [PubMed] [Google Scholar]
  34. Roux S. P., Tschopp T. B., Kuhn H., Steiner B., Hadváry P. Effects of heparin, aspirin and a synthetic platelet glycoprotein IIb-IIIa receptor antagonist (Ro 43-5054) on coronary artery reperfusion and reocclusion after thrombolysis with tissue-type plasminogen activator in the dog. J Pharmacol Exp Ther. 1993 Jan;264(1):501–508. [PubMed] [Google Scholar]
  35. Ruggeri Z. M., Houghten R. A., Russell S. R., Zimmerman T. S. Inhibition of platelet function with synthetic peptides designed to be high-affinity antagonists of fibrinogen binding to platelets. Proc Natl Acad Sci U S A. 1986 Aug;83(15):5708–5712. doi: 10.1073/pnas.83.15.5708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Satoh T., Yamashita Y., Kamiyama T., Arisawa M. Tetrafibricin: a nonpeptidic fibrinogen receptor inhibitor from Streptomyces neyagawaensis. (II). Its antiplatelet activities. Thromb Res. 1993 Dec 1;72(5):401–412. doi: 10.1016/0049-3848(93)90240-o. [DOI] [PubMed] [Google Scholar]
  37. Satoh T., Yamashita Y., Kamiyama T., Watanabe J., Steiner B., Hadváry P., Arisawa M. Tetrafibricin: a nonpeptidic fibrinogen receptor inhibitor from Streptomyces neyagawaensis (I). Its GPIIb/IIIa blockage on solid phase binding assay. Thromb Res. 1993 Dec 1;72(5):389–400. doi: 10.1016/0049-3848(93)90239-k. [DOI] [PubMed] [Google Scholar]
  38. Shattil S. J., Brass L. F. Induction of the fibrinogen receptor on human platelets by intracellular mediators. J Biol Chem. 1987 Jan 25;262(3):992–1000. [PubMed] [Google Scholar]
  39. Shattil S. J., Cunningham M., Hoxie J. A. Detection of activated platelets in whole blood using activation-dependent monoclonal antibodies and flow cytometry. Blood. 1987 Jul;70(1):307–315. [PubMed] [Google Scholar]
  40. Smyth S. S., Parise L. V. Regulation of ligand binding to glycoprotein IIb-IIIa (integrin alpha IIb beta 3) in isolated platelet membranes. Biochem J. 1993 Jun 15;292(Pt 3):749–758. doi: 10.1042/bj2920749. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Steiner B., Cousot D., Trzeciak A., Gillessen D., Hadváry P. Ca2+-dependent binding of a synthetic Arg-Gly-Asp (RGD) peptide to a single site on the purified platelet glycoprotein IIb-IIIa complex. J Biol Chem. 1989 Aug 5;264(22):13102–13108. [PubMed] [Google Scholar]
  42. Steiner B., Trzeciak A., Pfenninger G., Kouns W. C. Peptides derived from a sequence within beta 3 integrin bind to platelet alpha IIb beta 3 (GPIIb-IIIa) and inhibit ligand binding. J Biol Chem. 1993 Apr 5;268(10):6870–6873. [PubMed] [Google Scholar]
  43. Timmons S., Bednarek M. A., Kloczewiak M., Hawiger J. Antiplatelet "hybrid" peptides analogous to receptor recognition domains on gamma and alpha chains of human fibrinogen. Biochemistry. 1989 Apr 4;28(7):2919–2923. doi: 10.1021/bi00433a026. [DOI] [PubMed] [Google Scholar]
  44. Topol E. J., Plow E. F. Clinical trials of platelet receptor inhibitors. Thromb Haemost. 1993 Jul 1;70(1):94–98. [PubMed] [Google Scholar]

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