Publikationsserver der Universitätsbibliothek Marburg
Titel:Beiträge zur Inhibierung der Proproteinkonvertase Furin
Autor:Ivanova, Teodora
Weitere Beteiligte: Steinmetzer, Torsten (Prof. Dr.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0780
DOI: https://doi.org/10.17192/z2017.0780
URN: urn:nbn:de:hebis:04-z2017-07804
DDC:615 Pharmakologie, Therapeutik
Titel (trans.):A contribution to the inhibition of the proprotein convertase furin
Publikationsdatum:2018-08-08
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:

Zusammenfassung:
Aufgrund der vielfältigen Funktionen in zahlreichen pathologischen Prozessen ist Furin ein attraktives Zielmolekül zur Wirkstoffentwicklung. Obwohl eine dauerhafte Furinhemmung möglicherweise zu Nebenwirkungen führt, ist eine kurzzeitige oder mitelfristige Therapie akuter furinabhängiger Infektionen durch spezifische Hemmstoffe durchaus denkbar. Die antivirale oder antibakterielle Wirkung vieler Furininhibitoren wurde in Zellkulturen belegt. Die antivirale Aktivität ausgewählter Furininhibitoren wurde in unterschiedlichen Zellkulturtests untersucht. Bei den verwendeten Konzentrationen zeigten die Inhibitoren eine vernachlässigbare Zytotoxizität (Zellviabilität > 80 %). Furin ist eine Proproteinkonvertase, deren physiologische Aufgabe in der Prozessierung lebensnotwendiger Vorläuferproteine (Proproteine) besteht. Andererseits ist die Furinaktivität auch mit unterschiedlichen pathologischen Prozessen assoziiert. Dazu zählen einige Krebsarten, diverse Stoffwechselerkrankungen sowie verschiedene bakterielle und virale Infektionen. Daher ist Furin ein interessantes Zielmolekül für die Entwicklung entsprechender Arzneistoffe.

Bibliographie / References

  1. Bernatowicz, M.S., Wu, Y., and Matsueda, G.R. (1992). 1H-Pyrazole-1-carboxamidine hydrochloride an attractive reagent for guanylation of amines and its application to peptide synthesis. The Journal of Organic Chemistry 57, 2497-2502.
  2. Leduc, R., Molloy, S.S., Thorne, B.A., and Thomas, G. (1992). Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage. J Biol Chem 267, 14304-14308.
  3. Anderson, E.D., VanSlyke, J.K., Thulin, C.D., Jean, F., and Thomas, G. (1997). Activation of the furin endoprotease is a multiple-step process: requirements for acidification and internal propeptide cleavage. EMBO J 16, 1508-1518.
  4. Wang, H., Wang, H.S., and Liu, Z.P. (2011). Agents that induce pseudo-allergic reaction. Drug discoveries & therapeutics 5, 211-219.
  5. Jean, F., Stella, K., Thomas, L., Liu, G., Xiang, Y., Reason, A.J., and Thomas, G. (1998). alpha1- Antitrypsin Portland, a bioengineered serpin highly selective for furin: application as an antipathogenic agent. Proc Natl Acad Sci U S A 95, 7293-7298.
  6. Sperl, S., Jacob, U., Arroyo de Prada, N., Stürzebecher, J., Wilhelm, O.G., Bode, W., Magdolen, V., Huber, R., and Moroder, L. (2000). (4-aminomethyl)phenylguanidine derivatives as nonpeptidic highly selective inhibitors of human urokinase. Proc Natl Acad Sci U S A 97, 5113-5118.
  7. Arginine-rich peptides. An abundant source of membrane-permeable peptides having potential as carriers for intracellular protein delivery. J Biol Chem 276, 5836-5840.
  8. Kotthaus, J., Steinmetzer, T., van de Locht, A., and Clement, B. (2011). Analysis of highly potent amidine containing inhibitors of serine proteases and their N-hydroxylated prodrugs (amidoximes). J Enzyme Inhib Med Chem 26, 115-122.
  9. Khazdooz, L., Zarei, A., Aghaei, H., Azizi, G., and Gheisari, M.M. (2016). An efficient and selective method for the iodination and bromination of alcohols under mild conditions. Tetrahedron Letters 57, 168-171.
  10. Klimpel, K.R., Molloy, S.S., Thomas, G., and Leppla, S.H. (1992). Anthrax toxin protective antigen is activated by a cell surface protease with the sequence specificity and catalytic properties of furin. Proc Natl Acad Sci U S A 89, 10277-10281.
  11. Antibacterial activities of amphiphilic cyclic cell-penetrating peptides against multidrug-resistant pathogens. Mol Pharm 11, 3528-3536.
  12. Hancock, R.E., and Sahl, H.G. (2006). Antimicrobial and host-defense peptides as new anti- infective therapeutic strategies. Nat Biotechnol 24, 1551-1557.
  13. Lu, W., Zhang, W., Molloy, S.S., Thomas, G., Ryan, K., Chiang, Y., Anderson, S., and Laskowski, M., Jr. (1993). Arg15-Lys17-Arg18 turkey ovomucoid third domain inhibits human furin. J Biol Chem 268, 14583-14585.
  14. Dang, Q.D., and Di Cera, E. (1994). A simple activity assay for thrombin and hirudin. J Protein Chem 13, 367-373.
  15. Coppola, J.M., Bhojani, M.S., Ross, B.D., and Rehemtulla, A. (2008). A small-molecule furin inhibitor inhibits cancer cell motility and invasiveness. Neoplasia 10, 363-370.
  16. Mukhopadhyay, S., Kuhn, R.J., and Rossmann, M.G. (2005). A structural perspective of the flavivirus life cycle. Nat Rev Microbiol 3, 13-22.
  17. Judkins, B.D., Allen, D.G., Cook, T.A., Evans, B., and Sardharwala, T.E. (1996). A versatile synthesis of amidines from nitriles via amidoximes. Synth Comm 26, 4351-4367.
  18. Lättig-Tünnemann, G., Prinz, M., Hoffmann, D., Behlke, J., Palm-Apergi, C., Morano, I., Herce, H.D., and Cardoso, M.C. (2011). Backbone rigidity and static presentation of guanidinium groups increases cellular uptake of arginine-rich cell-penetrating peptides. Nat Commun 2, 453.
  19. Huang, K.H., Mangette, J., Barta, T., Hall, S.E., Veal, J., and Hughes, P. (2008). Benzene, Pyridine, and Pyridazine Derivatives. US 2008/0119457 A1.
  20. Molloy, S.S., Anderson, E.D., Jean, F., and Thomas, G. (1999). Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends Cell Biol 9, 28-35.
  21. Basak, A., Chen, A., Scamuffa, N., Mohottalage, D., Basak, S., and Khatib, A.M. (2010). Blockade of furin activity and furin-induced tumor cells malignant phenotypes by the chemically synthesized human furin prodomain. Curr Med Chem 17, 2214-2221.
  22. Cui, Y., Jean, F., Thomas, G., and Christian, J.L. (1998). BMP-4 is proteolytically activated by furin and/or PC6 during vertebrate embryonic development. EMBO J 17, 4735-4743.
  23. Stein, R.L. (1985). Catalysis by human leukocyte elastase: III. Steady-state kinetics for the hydrolysis of p-nitrophenyl esters. Arch Biochem Biophys 236, 677-680.
  24. Ramos-Molina, B., Lick, A.N., Nasrolahi Shirazi, A., Oh, D., Tiwari, R., El-Sayed, N.S., Parang, K., and Lindberg, I. (2015). Cationic Cell-Penetrating Peptides Are Potent Furin Inhibitors. PLoS One 10, e0130417.
  25. Milletti, F. (2012). Cell-penetrating peptides: classes, origin, and current landscape. Drug Discov Today 17, 850-860.
  26. Reissmann, S. (2014). Cell penetration: scope and limitations by the application of cell-penetrating peptides. J Pept Sci 20, 760-784.
  27. Watanabe, T., Watanabe, S., and Kawaoka, Y. (2010). Cellular networks involved in the influenza virus life cycle. Cell Host Microbe 7, 427-439.
  28. Hause, B.M., Collin, E.A., Liu, R., Huang, B., Sheng, Z., Lu, W., Wang, D., Nelson, E.A., and Li, F. (2014). Characterization of a novel influenza virus in cattle and Swine: proposal for a new genus in the Orthomyxoviridae family. MBio 5, e00031-00014.
  29. Neumann, U., Kubota, H., Frei, K., Ganu, V., and Leppert, D. (2004). Characterization of Mca- Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2, a fluorogenic substrate with increased specificity constants for collagenases and tumor necrosis factor converting enzyme. Anal Biochem 328, 166- 173.
  30. Schiebel, J., Gaspari, R., Sandner, A., Ngo, K., Gerber, H.D., Cavalli, A., Ostermann, A., Heine, A., and Klebe, G. (2017). Charges Shift Protonation: Neutron Diffraction Reveals that Aniline and 2-Aminopyridine Become Protonated Upon Binding to Trypsin. Angew Chem Int Ed Engl 56, 4887-4890.
  31. Rashad, A.A., Mahalingam, S., and Keller, P.A. (2014). Chikungunya virus: emerging targets and new opportunities for medicinal chemistry. J Med Chem 57, 1147-1166.
  32. Wu, Y., Yakar, S., Zhao, L., Hennighausen, L., and LeRoith, D. (2002). Circulating insulin-like growth factor-I levels regulate colon cancer growth and metastasis. Cancer Res 62, 1030-1035.
  33. Chiron, M.F., Fryling, C.M., and FitzGerald, D.J. (1994). Cleavage of pseudomonas exotoxin and diphtheria toxin by a furin-like enzyme prepared from beef liver. J Biol Chem 269, 18167-18176.
  34. Pallottini, V., Marino, M., and Ascenzi, P. (2002). Clonidine displacement from type 1 imidazoline receptor by p-aminobenzamidine, the prototype of trypsin-like serine protease inhibitors. IUBMB Life 54, 301-304.
  35. Gordon, V.M., Benz, R., Fujii, K., Leppla, S.H., and Tweten, R.K. (1997). Clostridium septicum alpha-toxin is proteolytically activated by furin. Infect Immun 65, 4130-4134.
  36. Mbikay, M., Sirois, F., Yao, J., Seidah, N.G., and Chretien, M. (1997). Comparative analysis of expression of the proprotein convertases furin, PACE4, PC1 and PC2 in human lung tumours. Br J Cancer 75, 1509-1514.
  37. Junqueira, R.G., Silva, E., and Mares-Guia, M. (1992). Competitive parabolic inhibition of bovine trypsin by bis-benzamidines. Braz J Med Biol Res 25, 873-887.
  38. Lei, J., Hansen, G., Nitsche, C., Klein, C.D., Zhang, L., and Hilgenfeld, R. (2016). Crystal structure of Zika virus NS2B-NS3 protease in complex with a boronate inhibitor. Science 353, 503-505.
  39. Ventura, E., Weller, M., and Burghardt, I. (2017). Cutting Edge: ERK1 Mediates the Autocrine Positive Feedback Loop of TGF-beta and Furin in Glioma-Initiating Cells. J Immunol 198, 4569- 4574.
  40. Design and characterization of hirulogs: a novel class of bivalent peptide inhibitors of thrombin. Biochemistry 29, 7095-7101.
  41. Kwiatkowska, A., Couture, F., Levesque, C., Ly, K., Desjardins, R., Beauchemin, S., Prahl, A., Lammek, B., Neugebauer, W., Dory, Y.L., et al. (2014). Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor. J Med Chem 57, 98-109.
  42. Kim, B.C., Hwang, S.Y., Lee, T.H., Chang, J.H., Choi, H.W., Lee, K.W., Choi, B.S., Kim, Y.K., Lee, J.H., Kim, W.S., et al. (2006). Development of a scalable synthetic route towards a thrombin inhibitor, LB30057. Org Process Res Dev 10, 881-886.
  43. Pappenheimer, A.M., Jr. (1977). Diphtheria toxin. Annu Rev Biochem 46, 69-94.
  44. Collier, R.J. (1975). Diphtheria toxin: mode of action and structure. Bacteriol Rev 39, 54-85.
  45. Feichtinger, K., Zapf, C., Sings, H.L., and Goodman, M. (1998b). Diprotected triflylguanidines: A new class of guanidinylation reagents. Journal of Organic Chemistry 63, 3804-3805.
  46. Peternel, L., Stempelj, M., Cerne, M., Zega, A., Obreza, A., Oblak, M., Drevensek, G., Budihna, M.V., Stanovnik, L., and Urleb, U. (2006). Direct thrombin inhibitors built on the azaphenylalanine scaffold provoke degranulation of mast cells. Thromb Haemost 95, 294-300.
  47. Qian, Z., Martyna, A., Hard, R.L., Wang, J., Appiah-Kubi, G., Coss, C., Phelps, M.A., Rossman, J.S., and Pei, D. (2016). Discovery and Mechanism of Highly Efficient Cyclic Cell-Penetrating Peptides. Biochemistry 55, 2601-2612.
  48. de Curtis, I., and Simons, K. (1988). Dissection of Semliki Forest virus glycoprotein delivery from the trans-Golgi network to the cell surface in permeabilized BHK cells. Proc Natl Acad Sci U S A 85, 8052-8056.
  49. Drews, J. (2000). Drug discovery: a historical perspective. Science 287, 1960-1964.
  50. Lee, J.E., and Saphire, E.O. (2009). Ebolavirus glycoprotein structure and mechanism of entry. Future Virol 4, 621-635.
  51. Kouretova, J., Hammamy, M.Z., Epp, A., Hardes, K., Kallis, S., Zhang, L., Hilgenfeld, R., Bartenschlager, R., and Steinmetzer, T. (2017). Effects of NS2B-NS3 protease and furin inhibition on West Nile and Dengue virus replication. J Enzyme Inhib Med Chem 32, 712-721.
  52. Qian, Z., Liu, T., Liu, Y.Y., Briesewitz, R., Barrios, A.M., Jhiang, S.M., and Pei, D. (2013). Efficient delivery of cyclic peptides into mammalian cells with short sequence motifs. ACS Chem Biol 8, 423-431.
  53. Bassi, D.E., Mahloogi, H., Al-Saleem, L., Lopez De Cicco, R., Ridge, J.A., and Klein-Szanto, A.J. (2001b). Elevated furin expression in aggressive human head and neck tumors and tumor cell lines. Mol Carcinog 31, 224-232.
  54. Hardes, K., Ivanova, T., Thaa, B., McInerney, G.M., Klokk, T.I., Sandvig, K., Künzel, S., Lindberg, I., and Steinmetzer, T. (2017). Elongated and Shortened Peptidomimetic Inhibitors of the Proprotein Convertase Furin. ChemMedChem 12, 613-620.
  55. Komiyama, T., and Fuller, R.S. (2000). Engineered eglin c variants inhibit yeast and human proprotein processing proteases, Kex2 and furin. Biochemistry 39, 15156-15165.
  56. Fittler, H., Depp, A., Avrutina, O., Dahms, S.O., Than, M.E., Empting, M., and Kolmar, H. (2015). Engineering a Constrained Peptidic Scaffold towards Potent and Selective Furin Inhibitors. Chembiochem 16, 2441-2444.
  57. Oh, D., Nasrolahi Shirazi, A., Northup, K., Sullivan, B., Tiwari, R.K., Bisoffi, M., and Parang, K. (2014a). Enhanced cellular uptake of short polyarginine peptides through fatty acylation and cyclization. Mol Pharm 11, 2845-2854.
  58. Mas, V., and Melero, J.A. (2013). Entry of enveloped viruses into host cells: membrane fusion. Subcell Biochem 68, 467-487.
  59. Becker, G.L. (2011). Entwicklung, Synthese und Charakterisierung neuartiger Furininhibitoren.
  60. Pond, A.L., and Nerbonne, J.M. (2001). ERG proteins and functional cardiac I(Kr) channels in rat, mouse, and human heart. Trends in cardiovascular medicine 11, 286-294.
  61. Evidence for involvement of furin in cleavage and activation of diphtheria toxin. J Biol Chem 268, 26461-26465.
  62. Joullié, M.M., and Lassen, K.M. (2010). Evolution of amide bond formation ARKIVOC viii, 189- 250.
  63. Yamanishi, Y., Boyle, D.L., Clark, M., Maki, R.A., Tortorella, M.D., Arner, E.C., and Firestein, G.S. (2002). Expression and regulation of aggrecanase in arthritis: the role of TGF-beta. J Immunol 168, 1405-1412.
  64. Sounni, N.E., Baramova, E.N., Munaut, C., Maquoi, E., Frankenne, F., Foidart, J.M., and Noel, A. (2002). Expression of membrane type 1 matrix metalloproteinase (MT1-MMP) in A2058 melanoma cells is associated with MMP-2 activation and increased tumor growth and vascularization. Int J Cancer 98, 23-28.
  65. Roebroek, A.J., Umans, L., Pauli, I.G., Robertson, E.J., van Leuven, F., Van de Ven, W.J., and Constam, D.B. (1998). Failure of ventral closure and axial rotation in embryos lacking the proprotein convertase Furin. Development 125, 4863-4876.
  66. International Human Genome Sequencing, C. (2004). Finishing the euchromatic sequence of the human genome. Nature 431, 931-945.
  67. Lindenbach, B.D., Thiel, H.J., and Rice, C.M. (2007). Flaviviridae: The Viruses and Their Replication. In Fields' virology, B.N. Fields, D.M. Knipe, and P.M. Howley, eds. (Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins), pp. 1101-1152.
  68. Chambers, T.J., Hahn, C.S., Galler, R., and Rice, C.M. (1990). Flavivirus genome organization, expression, and replication. Annu Rev Microbiol 44, 649-688.
  69. Jean, F., Boudreault, A., Basak, A., Seidah, N.G., and Lazure, C. (1995). Fluorescent peptidyl substrates as an aid in studying the substrate specificity of human prohormone convertase PC1 and human furin and designing a potent irreversible inhibitor. J Biol Chem 270, 19225-19231.
  70. Dönnecke, D., Schweinitz, A., Stürzebecher, A., Steinmetzer, P., Schuster, M., Stürzebecher, U., Nicklisch, S., Stürzebecher, J., and Steinmetzer, T. (2007). From selective substrate analogue factor Xa inhibitors to dual inhibitors of thrombin and factor Xa. Part 3. Bioorg Med Chem Lett 17, 3322- 3329.
  71. Inocencio, N.M., Moehring, J.M., and Moehring, T.J. (1994). Furin activates Pseudomonas exotoxin A by specific cleavage in vivo and in vitro. J Biol Chem 269, 31831-31835.
  72. Nakayama, K. (1997). Furin: a mammalian subtilisin/Kex2p-like endoprotease involved in processing of a wide variety of precursor proteins. Biochem J 327 ( Pt 3), 625-635.
  73. Thomas, G. (2002). Furin at the cutting edge: from protein traffic to embryogenesis and disease. Nat Rev Mol Cell Biol 3, 753-766.
  74. Cao, J., Rehemtulla, A., Pavlaki, M., Kozarekar, P., and Chiarelli, C. (2005). Furin directly cleaves proMMP-2 in the trans-Golgi network resulting in a nonfunctioning proteinase. J Biol Chem 280, 10974-10980.
  75. Garred, O., van Deurs, B., and Sandvig, K. (1995). Furin-induced cleavage and activation of Shiga toxin. J Biol Chem 270, 10817-10821.
  76. Podsiadlo, P., Komiyama, T., Fuller, R.S., and Blum, O. (2004). Furin inhibition by compounds of copper and zinc. J Biol Chem 279, 36219-36227.
  77. Bassi, D.E., Lopez De Cicco, R., Mahloogi, H., Zucker, S., Thomas, G., and Klein-Szanto, A.J. (2001a). Furin inhibition results in absent or decreased invasiveness and tumorigenicity of human cancer cells. Proc Natl Acad Sci U S A 98, 10326-10331.
  78. López-Vallejo, F., and Martínez-Mayorga, K. (2012). Furin inhibitors: importance of the positive formal charge and beyond. Bioorg Med Chem 20, 4462-4471.
  79. van de Ven, W.J., Voorberg, J., Fontijn, R., Pannekoek, H., van den Ouweland, A.M., van Duijnhoven, H.L., Roebroek, A.J., and Siezen, R.J. (1990). Furin is a subtilisin-like proprotein processing enzyme in higher eukaryotes. Mol Biol Rep 14, 265-275.
  80. Huang, Y.H., Lin, K.H., Liao, C.H., Lai, M.W., Tseng, Y.H., and Yeh, C.T. (2012). Furin overexpression suppresses tumor growth and predicts a better postoperative disease-free survival in hepatocellular carcinoma. PLoS One 7, e40738.
  81. Zhang, X., Fugere, M., Day, R., and Kielian, M. (2003). Furin processing and proteolytic activation of Semliki Forest virus. J Virol 77, 2981-2989.
  82. White, J.M., and Whittaker, G.R. (2016). Fusion of Enveloped Viruses in Endosomes. Traffic 17, 593-614.
  83. Thakkar, A., Trinh, T.B., and Pei, D. (2013). Global analysis of peptide cyclization efficiency. ACS combinatorial science 15, 120-129.
  84. Babcock, J.J., and Li, M. (2013). hERG channel function: beyond long QT. Acta Pharmacol Sin 34, 329-335.
  85. Sanguinetti, M.C., and Tristani-Firouzi, M. (2006). hERG potassium channels and cardiac arrhythmia. Nature 440, 463-469.
  86. Becker, G.L., Lu, Y., Hardes, K., Strehlow, B., Levesque, C., Lindberg, I., Sandvig, K., Bakowsky, U., Day, R., Garten, W., et al. (2012). Highly potent inhibitors of proprotein convertase furin as potential drugs for treatment of infectious diseases. J Biol Chem 287, 21992-22003.
  87. Paschalidou, K., Neumann, U., Gerhartz, B., and Tzougraki, C. (2004). Highly sensitive intramolecularly quenched fluorogenic substrates for renin based on the combination of L-2-amino- 3-(7-methoxy-4-coumaryl)propionic acid with 2,4-dinitrophenyl groups at various positions. Biochem J 382, 1031-1038.
  88. Stone, S.R., and Maraganore, J.M. (1992). Hirudin interactions with thrombin. In Thrombin: Structure and function, L.J. Berliner, ed. (New York: Plenum Press), pp. 219-256.
  89. Overington, J.P., Al-Lazikani, B., and Hopkins, A.L. (2006). How many drug targets are there? Nat Rev Drug Discov 5, 993-996.
  90. Lopez de Cicco, R., Bassi, D.E., Zucker, S., Seidah, N.G., and Klein-Szanto, A.J. (2005). Human carcinoma cell growth and invasiveness is impaired by the propeptide of the ubiquitous proprotein convertase furin. Cancer Res 65, 4162-4171.
  91. Leskovac, V. (2003a). Hyperbolic and parabolic inhibition. In Comprehensive enzyme kinetics, V. Leskovac, ed. (New York: Kluwer Academic/Plenum Publishers), pp. 95-110.
  92. McDermott, J.S., Salmen, H.J., Cox, B.F., and Gintant, G.A. (2002). Importance of species selection in arrythmogenic models of Q-T interval prolongation. Antimicrob Agents Chemother 46, 938-939.
  93. Kacprzak, M.M., Peinado, J.R., Than, M.E., Appel, J., Henrich, S., Lipkind, G., Houghten, R.A., Bode, W., and Lindberg, I. (2004). Inhibition of furin by polyarginine-containing peptides: nanomolar inhibition by nona-D-arginine. J Biol Chem 279, 36788-36794.
  94. Hallenberger, S., Bosch, V., Angliker, H., Shaw, E., Klenk, H.D., and Garten, W. (1992). Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Nature 360, 358-361.
  95. Komiyama, T., Coppola, J.M., Larsen, M.J., van Dort, M.E., Ross, B.D., Day, R., Rehemtulla, A., and Fuller, R.S. (2009). Inhibition of furin/proprotein convertase-catalyzed surface and intracellular processing by small molecules. J Biol Chem 284, 15729-15738.
  96. Anderson, E.D., Thomas, L., Hayflick, J.S., and Thomas, G. (1993). Inhibition of HIV-1 gp160- dependent membrane fusion by a furin-directed alpha 1-antitrypsin variant. J Biol Chem 268, 24887-24891.
  97. Basak, A., Cooper, S., Roberge, A.G., Banik, U.K., Chretien, M., and Seidah, N.G. (1999). Inhibition of proprotein convertases-1, -7 and furin by diterpines of Andrographis paniculata and their succinoyl esters. Biochem J 338 ( Pt 1), 107-113.
  98. Garten, W., Stieneke, A., Shaw, E., Wikström, P., and Klenk, H.D. (1989). Inhibition of proteolytic activation of influenza virus hemagglutinin by specific peptidyl chloroalkyl ketones. Virology 172, 25-31.
  99. Henneke, I., Greschus, S., Savai, R., Korfei, M., Markart, P., Mahavadi, P., Schermuly, R.T., Wygrecka, M., Stürzebecher, J., Seeger, W., et al. (2010). Inhibition of urokinase activity reduces primary tumor growth and metastasis formation in a murine lung carcinoma model. Am J Respir Crit Care Med 181, 611-619.
  100. Strongin, A., Pellecchia, M., and Barile, E. (2013). Inhibitors of furin and other pro-protein convertases. WO 2013/138666 A1.
  101. Steiner, D.F., Cunningham, D., Spigelman, L., and Aten, B. (1967). Insulin biosynthesis: evidence for a precursor. Science 157, 697-700.
  102. Opal, S.M., Artenstein, A.W., Cristofaro, P.A., Jhung, J.W., Palardy, J.E., Parejo, N.A., and Lim, Y.P. (2005). Inter-alpha-inhibitor proteins are endogenous furin inhibitors and provide protection against experimental anthrax intoxication. Infect Immun 73, 5101-5105.
  103. Hanson, S.R., and Harker, L.A. (1988). Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone. Proc Natl Acad Sci U S A 85, 3184-3188.
  104. Fuller, R.S., Brake, A.J., and Thorner, J. (1989). Intracellular targeting and structural conservation of a prohormone-processing endoprotease. Science 246, 482-486.
  105. Essalmani, R., Susan-Resiga, D., Chamberland, A., Abifadel, M., Creemers, J.W., Boileau, C., Seidah, N.G., and Prat, A. (2011). In vivo evidence that furin from hepatocytes inactivates PCSK9. J Biol Chem 286, 4257-4263.
  106. Julius, D., Brake, A., Blair, L., Kunisawa, R., and Thorner, J. (1984). Isolation of the putative structural gene for the lysine-arginine-cleaving endopeptidase required for processing of yeast prepro-alpha-factor. Cell 37, 1075-1089.
  107. Stone, S.R., and Hofsteenge, J. (1986). Kinetics of the inhibition of thrombin by hirudin. Biochemistry 25, 4622-4628.
  108. Creemers, J.W., and Khatib, A.M. (2008). Knock-out mouse models of proprotein convertases: unique functions or redundancy? Front Biosci 13, 4960-4971.
  109. Roebroek, A.J., Taylor, N.A., Louagie, E., Pauli, I., Smeijers, L., Snellinx, A., Lauwers, A., Van de Ven, W.J., Hartmann, D., and Creemers, J.W. (2004). Limited redundancy of the proprotein convertase furin in mouse liver. J Biol Chem 279, 53442-53450.
  110. Leskovac, V. (2003b). Linear inhibition. In Comprehensive enzyme kinetics, V. Leskovac, ed. (New York: Kluwer Academic/Plenum Publishers), pp. 73-94.
  111. Lepek, T., Kwiatkowska, A., Couture, F., Ly, K., Desjardins, R., Dory, Y., Prahl, A., and Day, R. (2017). Macrocyclization of a potent PACE4 inhibitor: Benefits and limitations. Eur J Cell Biol.
  112. Zhang, L., Goldhammer, C., Henkel, B., Panhaus, G., Zuehl, F., Jung, G., and Bayer, E. (1994). "Magic mixture", a powerful solvent system for solid-phase synthesis of difficult peptides. In Innovation and perspectives in solid phase synthesis, R. Epton, ed. (Birmingham, UK: Mayflower Worldwide, Ltd.), pp. 711-716.
  113. Moulard, M., and Decroly, E. (2000). Maturation of HIV envelope glycoprotein precursors by cellular endoproteases. Biochim Biophys Acta 1469, 121-132.
  114. DeWolfe, R.H., and Augustine, F.B. (1965). Mechanism of Hydrolysis of Ethyl Benzimidates in Acidic Solutions. Journal of Organic Chemistry 30, 699-702.
  115. Madani, F., Lindberg, S., Langel, U., Futaki, S., and Graslund, A. (2011). Mechanisms of cellular uptake of cell-penetrating peptides. J Biophys 2011, 414729.
  116. Rawlings, N.D., Waller, M., Barrett, A.J., and Bateman, A. (2014). MEROPS: the database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 42, D503-509.
  117. Molecular Validation of PACE4 as a Target in Prostate Cancer. Transl Oncol 4, 157-172.
  118. Oda, K. (2012). New families of carboxyl peptidases: serine-carboxyl peptidases and glutamic peptidases. J Biochem 151, 13-25.
  119. Sielaff, F., Than, M.E., Bevec, D., Lindberg, I., and Steinmetzer, T. (2011). New furin inhibitors based on weakly basic amidinohydrazones. Bioorg Med Chem Lett 21, 836-840.
  120. Becker, G.L., Hardes, K., and Steinmetzer, T. (2011). New substrate analogue furin inhibitors derived from 4-amidinobenzylamide. Bioorg Med Chem Lett 21, 4695-4697.
  121. Schweinitz, A., Stürzebecher, A., Stürzebecher, U., Schuster, O., Stürzebecher, J., and Steinmetzer, T. (2006). New substrate analogue inhibitors of factor Xa containing 4-amidinobenzylamide as P1 residue: part 1. Med Chem 2, 349-361.
  122. Dechantsreiter, M.A., Planker, E., Matha, B., Lohof, E., Holzemann, G., Jonczyk, A., Goodman, S.L., and Kessler, H. (1999). N-Methylated cyclic RGD peptides as highly active and selective alpha(V)beta(3) integrin antagonists. J Med Chem 42, 3033-3040.
  123. Schechter, I., and Berger, A. (1967). On the size of the active site in proteases. I. Papain. Biochem Biophys Res Commun 27, 157-162.
  124. Hinkes, S., Wuttke, A., Saupe, S.M., Ivanova, T., Wagner, S., Knörlein, A., Heine, A., Klebe, G., and Steinmetzer, T. (2016). Optimization of Cyclic Plasmin Inhibitors: From Benzamidines to Benzylamines. J Med Chem 59, 6370-6386.
  125. Gagnon, H., Beauchemin, S., Kwiatkowska, A., Couture, F., D'Anjou, F., Levesque, C., Dufour, F., Desbiens, A.R., Vaillancourt, R., Bernard, S., et al. (2014). Optimization of furin inhibitors to protect against the activation of influenza hemagglutinin H5 and Shiga toxin. J Med Chem 57, 29- 41.
  126. Andrushchenko, V.V., Vogel, H.J., and Prenner, E.J. (2007). Optimization of the hydrochloric acid concentration used for trifluoroacetate removal from synthetic peptides. J Pept Sci 13, 37-43.
  127. McBride, J.D., Watson, E.M., Brauer, A.B., Jaulent, A.M., and Leatherbarrow, R.J. (2002). Peptide mimics of the Bowman-Birk inhibitor reactive site loop. Biopolymers 66, 79-92.
  128. Machen, T.E., Leigh, M.J., Taylor, C., Kimura, T., Asano, S., and Moore, H.P. (2003). pH of TGN and recycling endosomes of H+/K+-ATPase-transfected HEK-293 cells: implications for pH regulation in the secretory pathway. Am J Physiol Cell Physiol 285, C205-214.
  129. Cameron, A., Appel, J., Houghten, R.A., and Lindberg, I. (2000). Polyarginines are potent furin inhibitors. J Biol Chem 275, 36741-36749.
  130. Bontemps, Y., Scamuffa, N., Calvo, F., and Khatib, A.M. (2007). Potential opportunity in the development of new therapeutic agents based on endogenous and exogenous inhibitors of the proprotein convertases. Med Res Rev 27, 631-648.
  131. Becker, G.L., Sielaff, F., Than, M.E., Lindberg, I., Routhier, S., Day, R., Lu, Y., Garten, W., and Steinmetzer, T. (2010). Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. J Med Chem 53, 1067-1075.
  132. Rockwell, N.C., Krysan, D.J., Komiyama, T., and Fuller, R.S. (2002). Precursor processing by kex2/furin proteases. Chem Rev 102, 4525-4548.
  133. Aronov, A.M. (2005). Predictive in silico modeling for hERG channel blockers. Drug Discov Today 10, 149-155.
  134. Garten, W., Hallenberger, S., Ortmann, D., Schäfer, W., Vey, M., Angliker, H., Shaw, E., and Klenk, H.D. (1994). Processing of viral glycoproteins by the subtilisin-like endoprotease furin and its inhibition by specific peptidylchloroalkylketones. Biochimie 76, 217-225.
  135. Henrich, S., Lindberg, I., Bode, W., and Than, M.E. (2005). Proprotein convertase models based on the crystal structures of furin and kexin: explanation of their specificity. J Mol Biol 345, 211- 227.
  136. Jin, W., Fuki, I.V., Seidah, N.G., Benjannet, S., Glick, J.M., and Rader, D.J. (2005). Proprotein convertases are responsible for proteolysis and inactivation of endothelial lipase. J Biol Chem 280, 36551-36559.
  137. Sarac, M.S., Peinado, J.R., Leppla, S.H., and Lindberg, I. (2004). Protection against anthrax toxemia by hexa-D-arginine in vitro and in vivo. Infect Immun 72, 602-605.
  138. Lin, H., Ah Kioon, M.D., Lalou, C., Larghero, J., Launay, J.M., Khatib, A.M., and Cohen-Solal, M. (2012). Protective role of systemic furin in immune response-induced arthritis. Arthritis Rheum 64, 2878-2886.
  139. Stadler, K., Allison, S.L., Schalich, J., and Heinz, F.X. (1997). Proteolytic activation of tick-borne encephalitis virus by furin. J Virol 71, 8475-8481.
  140. Krysan, D.J., Rockwell, N.C., and Fuller, R.S. (1999). Quantitative characterization of furin specificity. Energetics of substrate discrimination using an internally consistent set of hexapeptidyl methylcoumarinamides. J Biol Chem 274, 23229-23234.
  141. Skehel, J.J., and Wiley, D.C. (2000). Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69, 531-569.
  142. Clement, B. (2002). Reduction of N-hydroxylated compounds: amidoximes (N-hydroxyamidines) as pro-drugs of amidines. Drug Metab Rev 34, 565-579.
  143. Lee, R., Kermani, P., Teng, K.K., and Hempstead, B.L. (2001). Regulation of cell survival by secreted proneurotrophins. Science 294, 1945-1948.
  144. Cheng, Y., and Prusoff, W.H. (1973). Relationship between the inhibition constant (Ki) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22, 3099-3108.
  145. Couture, F., D'Anjou, F., Desjardins, R., Boudreau, F., and Day, R. (2012). Role of proprotein convertases in prostate cancer progression. Neoplasia 14, 1032-1042.
  146. Remacle, A.G., Gawlik, K., Golubkov, V.S., Cadwell, G.W., Liddington, R.C., Cieplak, P., Millis, S.Z., Desjardins, R., Routhier, S., Yuan, X.W., et al. (2010). Selective and potent furin inhibitors protect cells from anthrax without significant toxicity. Int J Biochem Cell Biol 42, 987-995.
  147. Willems, W.R., Kaluza, G., Boschek, C.B., Bauer, H., Hager, H., Schutz, H.J., and Feistner, H. (1979). Semliki forest virus: cause of a fatal case of human encephalitis. Science 203, 1127-1129.
  148. Kaufmann, J.E., Irminger, J.C., and Halban, P.A. (1995). Sequence requirements for proinsulin processing at the B-chain/C-peptide junction. Biochem J 310 ( Pt 3), 869-874.
  149. Kheradmand, F., Rishi, K., and Werb, Z. (2002). Signaling through the EGF receptor controls lung morphogenesis in part by regulating MT1-MMP-mediated activation of gelatinase A/MMP2. J Cell Sci 115, 839-848.
  150. Dahms, S.O., Jiao, G.S., and Than, M.E. (2017). Structural Studies Revealed Active Site Distortions of Human Furin by a Small Molecule Inhibitor. ACS Chem Biol.
  151. Hauel, N.H., Nar, H., Priepke, H., Ries, U., Stassen, J.M., and Wienen, W. (2002). Structure-based design of novel potent nonpeptide thrombin inhibitors. J Med Chem 45, 1757-1766.
  152. Phoo, W.W., Li, Y., Zhang, Z., Lee, M.Y., Loh, Y.R., Tan, Y.B., Ng, E.Y., Lescar, J., Kang, C., and Luo, D. (2016). Structure of the NS2B-NS3 protease from Zika virus after self-cleavage. Nat Commun 7, 13410.
  153. Dahms, S.O., Arciniega, M., Steinmetzer, T., Huber, R., and Than, M.E. (2016). Structure of the unliganded form of the proprotein convertase furin suggests activation by a substrate-induced mechanism. Proc Natl Acad Sci U S A 113, 11196-11201.
  154. White, J.M., Delos, S.E., Brecher, M., and Schornberg, K. (2008). Structures and mechanisms of viral membrane fusion proteins: multiple variations on a common theme. Crit Rev Biochem Mol Biol 43, 189-219.
  155. Eissler, S., Kley, M., Bachle, D., Loidl, G., Meier, T., and Samson, D. (2017). Substitution determination of Fmoc-substituted resins at different wavelengths. J Pept Sci 23, 757-762.
  156. Neunhoeffer, H., and Weischedel, F. (1971). Synthese von Amidrazonen aus Amidinen. Liebigs Ann Chem 749, 16-23.
  157. Kim, Y.A., Sharon, A., Chu, C.K., Rais, R.H., Al Safarjalani, O.N., Naguib, F.N., and el Kouni, M.H. (2007). Synthesis, biological evaluation and molecular modeling studies of N6- benzyladenosine analogues as potential anti-toxoplasma agents. Biochem Pharmacol 73, 1558- 1572.
  158. Angliker, H. (1995). Synthesis of tight binding inhibitors and their action on the proprotein- processing enzyme furin. J Med Chem 38, 4014-4018.
  159. Jiao, G.S., Cregar, L., Wang, J., Millis, S.Z., Tang, C., O'Malley, S., Johnson, A.T., Sareth, S., Larson, J., and Thomas, G. (2006). Synthetic small molecule furin inhibitors derived from 2,5- dideoxystreptamine. Proc Natl Acad Sci U S A 103, 19707-19712.
  160. Gouni-Berthold, I., Descamps, O.S., Fraass, U., Hartfield, E., Allcott, K., Dent, R., and Marz, W. (2016). Systematic review of published Phase 3 data on anti-PCSK9 monoclonal antibodies in patients with hypercholesterolaemia. Br J Clin Pharmacol 82, 1412-1443.
  161. Riegel, P., Ruimy, R., de Briel, D., Prevost, G., Jehl, F., Christen, R., and Monteil, H. (1995). Taxonomy of Corynebacterium diphtheriae and related taxa, with recognition of Corynebacterium ulcerans sp. nov. nom. rev. FEMS Microbiol Lett 126, 271-276.
  162. Blanchette, F., Day, R., Dong, W., Laprise, M.H., and Dubois, C.M. (1997). TGFbeta1 regulates gene expression of its own converting enzyme furin. J Clin Invest 99, 1974-1983.
  163. Seidah, N.G., Mayer, G., Zaid, A., Rousselet, E., Nassoury, N., Poirier, S., Essalmani, R., and Prat, A. (2008). The activation and physiological functions of the proprotein convertases. Int J Biochem Cell Biol 40, 1111-1125.
  164. Strauss, J.H., and Strauss, E.G. (1994). The alphaviruses: gene expression, replication, and evolution. Microbiol Rev 58, 491-562.
  165. Seidah, N.G., and Prat, A. (2012). The biology and therapeutic targeting of the proprotein convertases. Nat Rev Drug Discov 11, 367-383.
  166. Durant, G.J., Roe, A.M., and Green, A.L. (1970). The chemistry of guanidines and their actions at adrenergic nerve endings. Prog Med Chem 7, 124-213.
  167. Hill, A.V. (1913). The Combinations of Haemoglobin with Oxygen and with Carbon Monoxide. I. Biochem J 7, 471-480.
  168. Henrich, S., Cameron, A., Bourenkov, G.P., Kiefersauer, R., Huber, R., Lindberg, I., Bode, W., and Than, M.E. (2003). The crystal structure of the proprotein processing proteinase furin explains its stringent specificity. Nat Struct Biol 10, 520-526.
  169. Wender, P.A., Mitchell, D.J., Pattabiraman, K., Pelkey, E.T., Steinman, L., and Rothbard, J.B. (2000). The design, synthesis, and evaluation of molecules that enable or enhance cellular uptake: peptoid molecular transporters. Proc Natl Acad Sci U S A 97, 13003-13008.
  170. Dixon, M. (1953). The determination of enzyme inhibitor constants. Biochem J 55, 170-171.
  171. Hopkins, A.L., and Groom, C.R. (2002). The druggable genome. Nat Rev Drug Discov 1, 727-730.
  172. Than, M.E., Henrich, S., Bourenkov, G.P., Bartunik, H.D., Huber, R., and Bode, W. (2005). The endoproteinase furin contains two essential Ca2+ ions stabilizing its N-terminus and the unique S1 specificity pocket. Acta Crystallogr D Biol Crystallogr 61, 505-512.
  173. Luo, D., Vasudevan, S.G., and Lescar, J. (2015). The flavivirus NS2B-NS3 protease-helicase as a target for antiviral drug development. Antiviral Res 118, 148-158.
  174. Sarac, M.S., Cameron, A., and Lindberg, I. (2002). The furin inhibitor hexa-D-arginine blocks the activation of Pseudomonas aeruginosa exotoxin A in vivo. Infect Immun 70, 7136-7139.
  175. Lescar, J., Roussel, A., Wien, M.W., Navaza, J., Fuller, S.D., Wengler, G., Wengler, G., and Rey, F.A. (2001). The Fusion glycoprotein shell of Semliki Forest virus: an icosahedral assembly primed for fusogenic activation at endosomal pH. Cell 105, 137-148.
  176. Williams, J.W., and Morrison, J.F. (1979). The kinetics of reversible tight-binding inhibition. Methods Enzymol 63, 437-467.
  177. Atkins, G.J. (2013). The Pathogenesis of Alphaviruses. ISRN Virology 2013, 22.
  178. Hadfield, T.L., McEvoy, P., Polotsky, Y., Tzinserling, V.A., and Yakovlev, A.A. (2000). The pathology of diphtheria. J Infect Dis 181 Suppl 1, S116-120.
  179. Kaiser, B., Hauptmann, J., and Markwardt, F. (1987). The pharmacodynamics of synthetic thrombin inhibitors of the basic type substituted n-alpha arylsulfonylated phenylalanine amide. Pharmazie 42, 119-121.
  180. Abrami, L., Fivaz, M., Decroly, E., Seidah, N.G., Jean, F., Thomas, G., Leppla, S.H., Buckley, J.T., and van der Goot, F.G. (1998). The pore-forming toxin proaerolysin is activated by furin. J Biol Chem 273, 32656-32661.
  181. Benjannet, S., Rhainds, D., Hamelin, J., Nassoury, N., and Seidah, N.G. (2006). The proprotein convertase (PC) PCSK9 is inactivated by furin and/or PC5/6A: functional consequences of natural mutations and post-translational modifications. J Biol Chem 281, 30561-30572.
  182. Couture, F., Kwiatkowska, A., Dory, Y.L., and Day, R. (2015). Therapeutic uses of furin and its inhibitors: a patent review. Expert Opin Ther Pat 25, 379-396.
  183. Angliker, H., Wikstrom, P., Shaw, E., Brenner, C., and Fuller, R.S. (1993). The synthesis of inhibitors for processing proteinases and their action on the Kex2 proteinase of yeast. Biochem J 293 ( Pt 1), 75-81.
  184. Copeland, R.A. (2005). Tight binding inhibition. In Evaluation of enzyme inhibitors in drug discovery: a guide for medicinal chemists and pharmacologists, R.A. Copeland, ed. (Hoboken, New Jersey: John Wiley & Sons, Inc.), pp. 178-213.
  185. Wymore, R.S., Gintant, G.A., Wymore, R.T., Dixon, J.E., McKinnon, D., and Cohen, I.S. (1997). Tissue and species distribution of mRNA for the IKr-like K+ channel, erg. Circ Res 80, 261-268.
  186. Constam, D.B., and Robertson, E.J. (2000). Tissue-specific requirements for the proprotein convertase furin/SPC1 during embryonic turning and heart looping. Development 127, 245-254.
  187. Feichtinger, K., Sings, H.L., Baker, T.J., Matthews, K., and Goodman, M. (1998a). Triurethane- protected guanidines and triflyldiurethane-protected guanidines: New reagents for guanidinylation reactions. Journal of Organic Chemistry 63, 8432-8439.
  188. Heitz, F., Morris, M.C., and Divita, G. (2009). Twenty years of cell-penetrating peptides: from molecular mechanisms to therapeutics. Br J Pharmacol 157, 195-206.
  189. Rawlings, N.D., Barrett, A.J., and Finn, R. (2016). Twenty years of the MEROPS database of proteolytic enzymes, their substrates and inhibitors. Nucleic Acids Res 44, D343-350.
  190. Liu, Z.X., Fei, H., and Chi, C.W. (2004). Two engineered eglin c mutants potently and selectively inhibiting kexin or furin. FEBS Lett 556, 116-120.
  191. Madala, P.K., Tyndall, J.D., Nall, T., and Fairlie, D.P. (2010). Update 1 of: Proteases universally recognize beta strands in their active sites. Chem Rev 110, Pr1-31.
  192. Bernatowicz, M.S., Wu, Y., and Matsueda, G.R. (1993). Urethane protected derivatives of 1- guanylpyrazole for the mild and efficient preparation of guanidines. Tetrahedron Letters 34, 3389- 3392.
  193. Guevara-Salazar, J.A., Quintana-Zavala, D., Jiménez-Vázquez, H.A., and Trujillo-Ferrara, J. (2014). Use of the harmonic mean to the determination of dissociation constants of stereoisomeric mixtures of biologically active compounds. J Enzyme Inhib Med Chem 29, 884-894.
  194. Lim, S.P., and Shi, P.Y. (2013). West Nile virus drug discovery. Viruses 5, 2977-3006.
  195. Naqui, A. (1983). What does I50 mean? Biochem J 215, 429-430.
  196. Klebe, G. (2009). Wie wirken Arzneistoffe: Angriffspunkte für eine Therapie. In Wirkstoffdesign -Entwurf und Entwickling von Arzneistoffen, G. Klebe, ed. (Heidelberg: Spektrum Akademischer Verlag), pp. 335-349.
  197. X-ray structures of human furin in complex with competitive inhibitors. ACS Chem Biol 9, 1113- 1118.
  198. Yeast KEX2 endopeptidase correctly cleaves a neuroendocrine prohormone in mammalian cells. Science 241, 226-230.
  199. Petersen, L.R., Jamieson, D.J., and Honein, M.A. (2016). Zika Virus. N Engl J Med 375, 294-295.
  200. Dick, G.W., Kitchen, S.F., and Haddow, A.J. (1952). Zika virus. I. Isolations and serological specificity. Trans R Soc Trop Med Hyg 46, 509-520.
  201. Saiz, J.C., Vázquez-Calvo, A., Blázquez, A.B., Merino-Ramos, T., Escribano-Romero, E., and Martín-Acebes, M.A. (2016). Zika Virus: the Latest Newcomer. Frontiers in microbiology 7, 496.

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