Proteinase inhibitors from the european medicinal leech Hirudo medicinalis: Structural, functional and biomedical aspects

Abbink, 1991, Predominant role of neutrophils in the inactivation of α2-macroglobulin in arthritic joints, Arthritis Rheum., 34, 1139, 10.1002/art.1780340910 Adams, 1988, the medical leech: a page from the anellids of internal medicine, Ann. Intern. Med., 109, 399, 10.7326/0003-4819-109-5-399 Amiconi, 1987, Interaction between serine (pro)enzymes and macromolecular inhibitors: thermodynamic and kinetic aspects, 117 Antonini, 1983, Multiple intermediates in the reaction of bovine β-trypsin with bovine pancreatic trypsin inhibitor (Kunitz), Biopolymers, 22, 363, 10.1002/bip.360220147 Antonini, 1983, Transient removal of proflavine inhibition of bovine β-trypsin by the bovine basic pancreatic trypsin inhibitor (Kunitz), J. Biol. Chem., 258, 4676, 10.1016/S0021-9258(18)32471-2 Appella, 1988, Structure and function of epidermal growth factor-like regions in proteins, FEBS Lett., 231, 1, 10.1016/0014-5793(88)80690-2 Ascenzi, 1991, Binding of the recombinant proteinase inhibitor eglin c from leech Hirudo medicinalis to serine (pro)enzymes: a comparative thermodynamic study, J. Mol. Recogn., 4, 113, 10.1002/jmr.300040402 Ascenzi, 1986, Binding of porcine pancreatic secretory trypsin inhibitor to bovine β-trypsin: a kinetic study, Biopolymers, 25, 2325, 10.1002/bip.360251210 Ascenzi, 1992, Binding of hirudin to human α, β and γ-thrombin: a comparative kinetic and thermodynamic study, J. Mol. Biol., 225, 177, 10.1016/0022-2836(92)91034-M Ascenzi, 1992, Inhibition of human α-, β- and γ-thrombin by mono-, bis-, tris- and tetra-benzamidine structures: thermodynamic study, J. Enzyme Inhibit., 6, 131, 10.3109/14756369209040744 Ascenzi, 1988, Binding of the bovine basic pancreatic trypsin inhibitor (Kunitz) to human α-, β- and γ-thrombin: a kinetic and thermodynamic study, Biochim. Biophys. Acta, 956, 156, 10.1016/0167-4838(88)90262-2 Atkins, 1994 Auerswald, 1988, Expression, isolation and characterization of recombinant (Arg-15, Glu-52) aprotinin, Biol. Chem. Hoppe-Seyler, 369, 27 Auerswald, 1994, Recombinant leech-derived tryptase inhibitor: construction, production, protein chemical characterization and inhibition of HIV-1 replication, Biol. Chem. Hoppe-Seyler, 375, 695, 10.1515/bchm3.1994.375.10.695 Ayala, 1994, Molecular recognition by thrombin: role of the slow → fast transition, site-specific ion binding energetics and thermodynamic mapping of structural components, J. Mol. Biol., 235, 733, 10.1006/jmbi.1994.1024 Badimon, 1994, Thrombin in arterial thrombosis, Haemostasis, 24, 69 Bagdy, 1976, Hirudin, Meth. Enzymol., 45, 669, 10.1016/S0076-6879(76)45057-7 Baird, 1986, O2 Metabolites and neutrophil elastase synergistically cause edematous injury in isolated rat lungs, J. Appl. Physiol., 61, 2224, 10.1152/jappl.1986.61.6.2224 Banda, 1987, Inactivation of human α1-proteinase inhibitor by macrophage elastase, J. Clin. Invest., 79, 1314, 10.1172/JCI112955 Banner, 1994, Serine proteases: 3D structures, mechanisms of action and inhibitors, 27 Bar-Shavit, 1989, Binding of thrombin to subendothelial extracellular matrix: protection and expression of functional properties, 84, 1096 Batchelor, 1984, The salvage of congested skin flaps by the application of leeches, Br. J. Plast. Surg., 37, 358, 10.1016/0007-1226(84)90079-1 Bates, 1989, Medicinal leech therapy: an overview, Orthop. Nursing, 8, 12, 10.1097/00006416-198903000-00003 Beatty, 1980, Kinetics of association of serine proteinases with native and oxidized α1-proteinase inhibitor and α1-antichymotrypsin, J. Biol. Chem., 255, 3931, 10.1016/S0021-9258(19)85615-6 Becker, 1992, Thrombin antagonists and antiplatelet agents, Am. J. Cardiol., 69, 39A, 10.1016/0002-9149(92)91170-9 Berrettini, 1987, Initiation of coagulation and relationships between intrinsic and extrinsic coagulation pathways, 473 Betz, 1991, Ionic interactions in the formation of the thrombin-hirudin complex, Biochem. J., 275, 801, 10.1042/bj2750801 Betz, 1991, Role of interactions involving C-terminal nonpolar residues of hirudin in the formation of the thrombin-hirudin complex, Biochemistry, 30, 9848, 10.1021/bi00105a006 Betz, 1992, pH Dependence of the interaction of hirudin with thrombin, Biochemistry, 31, 1168, 10.1021/bi00119a028 Betz, 1994, Contribution of interactions with the core domain of hirudin to the stability of its complex with thrombin, Biochem. J., 298, 507, 10.1042/bj2980507 Betzel, 1993, Structure of the proteinase inhibitor eglin c with hydrolysed reactive centre at 2.0 Å resolution, FEBS Lett., 317, 185, 10.1016/0014-5793(93)81273-3 Bichler, 1991, Studies for revealing a possible sensitization to hirudin after repeated intravenous injection in baboons, Thromb. Res., 61, 39, 10.1016/0049-3848(91)90167-U Bieth, 1974, Some kinetic consequences of the tight binding of protein: proteinaseinhibitors to proteolytic enzymes and their application to the determination of dissociation constants, 463 Bieth, 1980, In vivo significance of kinetic constants of macromolecular proteinase inhibitors, Bull. Eur. Physiopath. Resp., 16, 183 Bigler, 1993, Binding of amino acid side chains to preformed cavities: interaction of serine proteinases with turkey ovomucoid third domains with coded and noncoded P1 residues, Protein Sci., 2, 786, 10.1002/pro.5560020509 Bode, 1991, Ligand binding: proteinase-protein inhibitor interactions, Curr. Opin. Struct. Biol., 1, 45, 10.1016/0959-440X(91)90010-Q Bode, 1992, Natural protein proteinase inhibitors and their interaction with proteinases, Eur. J. Biochem., 204, 433, 10.1111/j.1432-1033.1992.tb16654.x Bode, 1992, X-Ray crystal structures of human α-thrombin and of human thrombin-hirudin complex, 3 Bode, 1992, The refined 1.9Å X-ray crystal structure of d-Phe-Pro-Arg chloromethylketone inhibited human α-thrombin: structure analysis, overall structure, electrostatic properties, detailed active site geometry, structure-function relationships, Protein Sci., 1, 426, 10.1002/pro.5560010402 Bode, 1989, The refined 1.9 Å crystal structure of human α-thrombin. Interaction with d-Phe-Pro-Arg chlorome-thylketone and significance of the tur-pro-pro-trp insertion segment, EMBO J., 8, 3467, 10.1002/j.1460-2075.1989.tb08511.x Bode, 1986, Refined 1.2 Å cyystal structure of the complex formed between subtilisin Carlsberg and the inhibitor eglin c: molecular structure of eglin and its detailed interaction with subtilisin, EMBO J., 5, 813, 10.1002/j.1460-2075.1986.tb04286.x Bode, 1987, The high-resolution X-ray crystal structure of the complex formed between subtilisin Carlsberg and eglin c, an elastase inhibitor from the leech Hirudo medicinalis: structural analysis, subtilisin structure and interface geometry, Eur. J. Biochem., 166, 673, 10.1111/j.1432-1033.1987.tb13566.x Bodong, 1905, Über Hirushin, Arch. Exp. Pathol. Pharmacol., 52, 242, 10.1007/BF01837789 Bolognesi, 1987, Structural bases for the recognition of inhibitors by serine proteinases and their zymogens, 81 Bolognesi, 1982, Three-dimensional structure of the complex between pancreatic secretory inhibitor (Kazal-type) and trypsinogen at 1.8 Å resolution. Structure solution, crystallographic refinement and preliminary structural interpretation, J. Mol. Biol., 162, 839, 10.1016/0022-2836(82)90550-2 Bolognesi, 1990, X-ray crystal strusture of the bovine α-chymotrypsin/eglin c complex at 2.6 Å resolution, J. Mol. Recogn., 3, 163, 10.1002/jmr.300030405 Braun, 1986, A brief review of the biochemistry and pharmacology of eglin c, an elastase inhibitor, Eur. J. Respir. Dis., 146, 541 Braun, 1987, Interaction of eglin c with polymorphonuclear cells: evidence for binding to the cell surface, Biol. Chem. Hoppe-Seyler, 368, 155, 10.1515/bchm3.1987.368.1.155 Braun, 1987, Kinetic studies on the interaction of eglin c with human leukocyte elastase and cathepsin G, Biol. Chem. Hoppe-Seyler, 368, 299, 10.1515/bchm3.1987.368.1.299 Braun, 1988, Use of site-directed mutagenesis to investigate the basis for the specificity of hirudin, Biochemistry, 27, 6517, 10.1021/bi00417a048 Butkowski, 1977, Primary structure of prethrombin 2 and α-thrombin, J. Biol. Chem., 252, 4942, 10.1016/S0021-9258(17)40144-X Cannon, 1993, Thrombolysis in acute myocardial infarction, J. Am. Coll. Cardiol., 21, 740 Chang, 1983, The functional domain of hirudin: a thrombin-specific inhibitor, FEBS Lett., 164, 307, 10.1016/0014-5793(83)80307-X 1993 Chesebro, 1987, The therapeutic challenge of plaque rupture: value of biochemical markers, J. Am. Coll. Cardiol., 10, 1005, 10.1016/S0735-1097(87)80337-6 Chignard, 1993, Leukocyte elastase-mediated release of von Willebrand factor from cultured endothelial cells, Eur. Respir. J., 6, 791, 10.1183/09031936.93.06060791 Church, 1991, Chimeric antithrombin peptide: characterization of an Arg-Gly-Asp- and hirudin carboxyl terminus-containing synthetic peptide, J. Biol. Chem., 266, 11975, 10.1016/S0021-9258(18)99052-6 Clore, 1987, The determination of the three-dimensional structure of barley serine proteinase inhibitor 2 by nuclear magnetic resonance, distance geometry and restrained molecular dynamics, Protein Eng., 1, 305, 10.1093/protein/1.4.305 Clore, 1987, Comparison of the solution and X-ray structures of barley serine proteinase inhibitor 2, Protein. Eng., 1, 313, 10.1093/protein/1.4.313 Coletta, 1990, Bovine trypsinogen activation; a thermodynamic study, Biophys. Chem., 37, 355, 10.1016/0301-4622(90)88034-P Collet, 1991, In vitro studies of elastin-fibrin biomaterial degradation: preservative effects of protease inhibitors and antibiotics, Biomaterials, 12, 763, 10.1016/0142-9612(91)90027-8 Connolly, 1992, Shape distribution of protein topography, Biopolymers, 32, 1215, 10.1002/bip.360320911 Creighton, 1989, Functional evolutionary divergence of proteolytic enzymes and their inhibitors, TIBS, 14, 319 Cutruzzola', 1993, Selective oxidation of Met-192 in bovine α-chymotrypsin: effect on catalytic and inhibitor binding properties, Biochim. Biophys. Acta, 1161, 201, 10.1016/0167-4838(93)90214-C Dautzer, 1988, Crystal Structure of a complex between thermitase from Thermoactinomyces vulgaris and the leech inhibitor eglin c, FEBS Lett., 236, 171, 10.1016/0014-5793(88)80309-0 Dauter, 1991, Complex between the subtilisin from a mesophilic bacterium and the leech inhibitor eglin c, Acta Crystallogr., B47, 707, 10.1107/S0108768191004202 Davie, 1991, The coagulation cascade: inhibition, maintenance and regulation, Biochemistry, 30, 10364, 10.1021/bi00107a001 De Cristofaro, 1992, Modulation of thrombin-hirudin interaction by specific ion effects, J. Mol. Biol., 226, 263, 10.1016/0022-2836(92)90138-A De Cristofaro, 1993, The linkage between binding of the C-terminal domain of hirudin and amidase activity in human α-thrombin, Biochem. J., 289, 485, 10.1042/bj2890475 Dean, 1989, Control of exogenous proteinases and their inhibitors at the macrophage cell surface, Biochim. Biophys. Acta, 992, 174, 10.1016/0304-4165(89)90007-X Dean, 1989, Free radicals inactivate human neutrophil elastase and its inhibitors with a comparable efficiency, Biochem. Biophys. Res. Commun., 159, 821, 10.1016/0006-291X(89)90068-5 Degen, 1983, Characterization of the complementary deoxyribonucleic acid and gene coding for human prothrombin, Biochemistry, 22, 2087, 10.1021/bi00278a008 Dennis, 1990, Use of fragments of hirudin to investigate thrombin-hirudin interaction, Eur. J. Biochem., 188, 61, 10.1111/j.1432-1033.1990.tb15371.x Devereux, 1984, A comprehensive set of sequence analysis programs for the VAX, Nucleic Acids Res., 12, 387, 10.1093/nar/12.1Part1.387 Dodt, 1988, Interaction of site specific hirudin variants with α-thrombin, FEBS Lett., 229, 87, 10.1016/0014-5793(88)80803-2 Dodt, 1990, Distinct binding sites of ala48-hirudin1–47 and ala48-hirudin48–65 on α-thrombin, J. Biol. Chem., 265, 713, 10.1016/S0021-9258(19)40108-7 Dodt, 1984, The complete amino acid sequence of hirudin: a thrombin specific inhibitor, FEBS Lett., 165, 180, 10.1016/0014-5793(84)80165-9 Dodt, 1985, The complete covalent structure of hirudin: localization of the disulfide bonds, Biol. Chem. Hoppe-Seyler, 366, 379, 10.1515/bchm3.1985.366.1.379 Dodt, 1987, Influence of chain shortening on the inhibitor properties of hirudin and eglin c, Biol. Chem. Hoppe-Seyler, 368, 1447, 10.1515/bchm3.1987.368.2.1447 Dunwiddie, 1993, Purification and characterization of inhibitors of blood coagulation factor Xa from haematophagus organisms, Meth. Enzymol., 223, 291, 10.1016/0076-6879(93)23052-O Duswald, 1982, Pathophysiology and pathobiochemistry of sepsis and septic shock: new findings on the importance of proteinase release and the possibilities for treatment, Intern. Devel. Diagn. Therapy, 2, 1 Eklund, 1993, Mast cell proteases, 241 Electricwala, 1993, The complete amino acid sequence of a hirudin variant from the leech Hirudinaria manillensis, J. Protein Chem., 12, 365, 10.1007/BF01028198 Electricwala, 1993, Biochemical characterization of a pancreatic elastase inhibitor from the leech Hirudinaria manillensis, J. Enzyme Inhib., 6, 293, 10.3109/14756369309020179 Elion, 1986, Proteolytic derivatives of thrombin, Ann. N.Y. Acad. Sci., 485, 16, 10.1111/j.1749-6632.1986.tb34564.x Engemann, 1981, Phylum annelida, class III: Hirudo medicinalis, the medical leech, 420 Esmon, 1982, Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C, J. Biol. Chem., 257, 859, 10.1016/S0021-9258(19)68276-1 Esposito, 1988, Protease inhibitor eglin c affects superoxide anion release but not bacterial killing by human polymorphonuclear leukocytes, Exp. Lung Res., 14, 743, 10.3109/01902148809087841 Esposito, 1987, Effect of the elastase inhibitor, eglin c, on antibacterial mechanisms in experimental pneumonia: description of a system to quantitate phagocytic and bactericidal activity of resident murine alveolar macrophages in vivo, Am. Rev. Respir. Dis., 135, 676 Faller, 1990, Kinetics of the inhibition of human pancreatic elastase by recombinant eglin c, Biochem. J., 270, 639, 10.1042/bj2700639 Fareed, 1989, Development perspectives for recombinant hirudin as an antithrombotic agent, Biol. Clin. Hematol., 11, 143 Fenton, 1986, Thrombin, Ann. N.Y. Acad. Sci., 485, 5, 10.1111/j.1749-6632.1986.tb34563.x Fenton, 1988, Thrombin bioregulatory functions, Adv. Clin. Enzymol., 6, 186 Fenton, 1989, Thrombin interactions with hirudin, Semin. Thromb. Hemost., 15, 265, 10.1055/s-2007-1002718 Fink, 1986, Inhibition of mast cell chymase by eglin c and antileukoprotease (HUSI-I), Biol. Chem. Hoppe-Seyler, 367, 567, 10.1515/bchm3.1986.367.2.567 Fink, 1986, The primary structure of bdellin B-3 from the leech Hirudo medicinalis: bdellin B-3 is a compact proteinase inhibitor of a ‘non-classical’ Kazal type; it is present in the leech in a high molecular mass form, Biol. Chem. Hoppe-Seyler, 367, 1235, 10.1515/bchm3.1986.367.2.1235 Finkelstein, 1989, The price of lost freedom: entropy of bimolecular complex formation, Protein Eng., 3, 1, 10.1093/protein/3.1.1 Fiorucci, 1995, Evidence for multiple interacting binding sites in bovine tryptase, FEBS Lett., 363, 81, 10.1016/0014-5793(95)00286-I Folkers, 1989, Solution structure of recombinant hirudin and the Lys47 → Glu mutant. A nuclear magnetic resonance and hybrid distance geometry dynamical simulated annealing study, Biochemistry, 28, 2601, 10.1021/bi00432a038 Foucher, 1981, Distal digital replantation: one of the best indications for microsurgery, Int. J. Microsurg., 3, 263 Fox, 1993, Anticoagulant activity of hirulog, a direct thrombin inhibitor, in humans, Thromb. Haemostas., 69, 157, 10.1055/s-0038-1651573 Friedrich, 1993, A Kazal-type inhibitor with thrombin specificity from Rhodnius prolixus, J. Biol. Chem., 268, 16216, 10.1016/S0021-9258(19)85408-X Frigerio, 1992, Crystal and molecular structure of the bovine α-chymotrypsin-eglin c complex at 2.0 Å resolution, J. Mol. Biol., 225, 107, 10.1016/0022-2836(92)91029-O Fritz, 1988, Human mucus proteinase inhibitor, Biol. Chem. Hoppe-Seyler, 369, 79 Fritz, 1969, Über das vorkommen eines trypsin-plasmin-inhibitors in hirudin, Hoppe-Seyler's Z. Physiol. Chem., 350, 91 Frommherz, 1991, Heparin strongly decreases the rate of inhibition of neutrophil elastase by α1-proteinase inhibitor, J. Biol. Chem., 266, 15356, 10.1016/S0021-9258(18)98623-0 Fujinaga, 1987, Crystal and molecular structures of the complex of α-chymotrypsin with its inhibitor turkey ovomucoid third domain at 1.8 Å resolution, J. Mol. Biol., 195, 397, 10.1016/0022-2836(87)90659-0 Fukusen, 1987, Kinetic studies on the inhibition of mast cell chymase by natural serine protease inhibitors: indications for potential biological functions of these inhibitors, Biochem. Med. Metab. Biol., 38, 165, 10.1016/0885-4505(87)90076-4 Gardell, 1993, Vampire bat salivary plasminogen activator, Meth. Enzymol., 223, 233, 10.1016/0076-6879(93)23049-S Garrison, 1914 Goddard, 1991, R-[N-acetyl]eglin c:poly(oxyethylene) conjugates: preparation, plasma persistence, and urinary excretion, J. Pharm. Sci., 80, 1171, 10.1002/jps.2600801215 Goldstein, 1986, Serine protease inhibitors of north american leechs, Comp. Biochem. Physiol., 84B, 117 Gros, 1989, Crystallographic refinement by incorporation of molecular dynamics: thermostable serine proteinase thermitase complexed with eglin c, Acta Crystallogr., B45, 488, 10.1107/S0108768189006038 Gros, 1989, Molecular dynamics refinement of a thermitase-eglin c complex at 1.98 Å resolution and comparison of two crystal forms that differ in calcium content, J. Mol. Biol., 210, 347, 10.1016/0022-2836(89)90336-7 Gros, 1992, Effects of eglin c binding to thermitase: three-dimensional structure comparison of native thermitase and thermitase eglin c complexes, Proteins, 12, 63, 10.1002/prot.340120108 Grütter, 1990, Crystal structure of the thrombin-hirudin complex. A novel mode of serine proteinase inhibition, EMBO J., 9, 2361, 10.1002/j.1460-2075.1990.tb07410.x Hansen, 1994, Neutrophil mediated damage to isolated myocites after anoxia and reoxygenation, Cardiovasc. Res., 28, 565, 10.1093/cvr/28.4.565 Harmon, 1985, Thrombin binds to a high-affinity 900000 dalton site on human platelets, Biochemistry, 24, 58, 10.1021/bi00322a010 Haruyama, 1989, The conformation of recombinant desulfatohirudin in aqueous solution determined by nuclear magnetic resonance, Biochemistry, 28, 4301, 10.1021/bi00436a027 Harvey, 1986, Cloning and expression of a cDNA coding for the anticoagulant hirudin from the bloodsucking leech, Hirudo medicinalis, 83, 1084 Hauptmann, 1993, Anticoagulant and antithrombotic action of the factor Xa inhibitor antistasin (ATS), Thromb. Res., 71, 169, 10.1016/0049-3848(93)90183-O Hauptmann, 1993, Anticoagulant potential of synthetic and recombinant inhibitors of factor Xa and thrombin in vitro, Blood Coagul. Fibrinolysis, 4, 577, 10.1097/00001721-199308000-00008 Haycraft, 1884, Über die einwirkung eines secretes des officinalen blutegels auf die gerinnbarkeit des blutes, Naunyn-Schmiedebergs Arch. Exp. Pathol. Pharmakol., 18, 209, 10.1007/BF01833843 Hecht, 1991, Three-dimensional structure of the complexes between bovine chymotrypsinogen A and two recombinant variants of human pancreatic secretory trypsin inhibitor (Kazal-type), J. Mol. Biol., 220, 711, 10.1016/0022-2836(91)90112-J Heidtmann, 1986, Human α1-proteinase inhibitor, 442 Heinz, 1992, Changing the inhibitory specificity and function of the proteinase inhibitor eglin c by site-directed mutagenesis: functional and structural investigation, Biochemistry, 31, 8755, 10.1021/bi00152a011 Heinz, 1989, Crystallization of human leukocyte elastase with its inhibitor Pro44-eglin c, J. Mol. Biol., 207, 641, 10.1016/0022-2836(89)90474-9 Heinz, 1991, Refined crystal structures of subtilisin Novo in complex with wild-type and two mutant eglins: comparison with other serine proteinase complexes, J. Mol. Biol., 217, 353, 10.1016/0022-2836(91)90549-L Hipler, 1992, X-ray crystal structure of the serine proteinase inhibitor eglin c at 1.95 Å resolution, FEBS Lett., 309, 139, 10.1016/0014-5793(92)81082-W Hirsh, 1991, Heparin, N. Engl. J. Med., 324, 1565, 10.1056/NEJM199105303242206 1982 Ho, 1986, Internal thermodynamics of position 51 mutants and natural variants of tyrosyl-tRNA synthetase, Biochemistry, 25, 1891, 10.1021/bi00356a009 Hoffmann, 1984, Inhibition of the thrombin-platelet reaction by hirudin, Haemostasis, 14, 164 Hofmann, 1992, Site-directed mutagenesis of the leech-derived factor Xa inhibitor antistasin, Biochem. J., 287, 943, 10.1042/bj2870943 Huber, 1978, Structural basis of activation and action of trypsin, Acc. Chem. Res., 11, 114, 10.1021/ar50123a006 Hyberts, 1990, Sequence-specific 1H NMR assignments and secondary structure of eglin c, Biochemistry, 29, 1465, 10.1021/bi00458a018 Hyberts, 1992, The solution structure of eglin c based on measurements of many NOE and coupling constants and its comparison with X-ray structures, Protein Sci., 1, 736, 10.1002/pro.5560010606 Hyberts, 1987, Stereospecific assignments of side-chain protons and characterization of torsion angles in eglin c, Eur. J. Biochem., 164, 625, 10.1111/j.1432-1033.1987.tb11173.x Inauen, 1990, Anoxia-reoxygenation-induced, neutrophyl-mediated endothelial cell injury: role of elastase, Am. J. Physiol., 259, H925 Jackman, 1992, Intrinsic fluorescence changes and rapid kinetics of the reaction of thrombin with hirudin, J. Biol. Chem., 267, 15375, 10.1016/S0021-9258(19)49544-6 Janin, 1990, The structure of protein-protein recognition sites, J. Biol. Chem., 265, 16027, 10.1016/S0021-9258(17)46181-3 Janin, 1995, Elusive affinities, Proteins, 21, 30, 10.1002/prot.340210105 Janoff, 1985, Elastases and emphysema: current assessment of the protease-antiprotease hypothesis, Am. Rev. Resp. Dis., 132, 417 Janoff, 1985, Elastase in injury, Annu. Rev. Med., 36, 207, 10.1146/annurev.me.36.020185.001231 Janus, 1983, Promotion of thrombin-catalyzed activation of factor XII by fibrinogen, Biochemistry, 22, 6269, 10.1021/bi00295a035 Jochum, 1981, Clotting and other plasma factors in experimental endotoxemia: inhibition of degradation by exogenous proteinase inhibitors, Eur. Surg. Res., 13, 152, 10.1159/000128181 Jochum, 1986, Pathobiochemistry of sepsis: role of proteinases, proteinase inhibitors and oxidizing agents, Behring Inst. Mitt., 121 Jonassen, 1982, Identification of the reactive sites in two homologous serine proteinase inhibitors isolated from barley, Carlsberg Res. Commun., 47, 199, 10.1007/BF02907871 Johnson, 1994, Hirudin: clinical potential of a thrombin inhibitor, Annu. Rev. Med., 45, 165, 10.1146/annurev.med.45.1.165 Johnson, 1978, Structural evidence for methionine at the reactive site of human α1-proteinase inhibitor, J. Biol. Chem., 253, 7142, 10.1016/S0021-9258(17)34475-7 Johnson, 1979, The oxidative inactivation of human α1-proteinase inhibitor, J. Biol. Chem., 254, 4022, 10.1016/S0021-9258(18)50689-X Junger, 1992, Inhibition of human, ovine, and baboon neutrophil elastase with eglin c and secretory leukocyte proteinase inhibitor, Biol. Chem. Hoppe-Seyler, 373, 119, 10.1515/bchm3.1992.373.1.119 Junger, 1989, Reasons for the ineffectiveness of eglin c to ameliorate endotoxin shock in sheep, Prog. Clin. Biol. Res., 308, 953 Kanayama, 1990, Inactivation of human tumour cell pro-urokinase by granulocyte elastase, Jpn J. Cancer Res., 81, 994, 10.1111/j.1349-7006.1990.tb03337.x Kao, 1988, Proteinase 3: a distinct human polymorphonuclear leukocyte proteinase that produces emphysema in hamsters, J. Clin. Invest., 82, 1963, 10.1172/JCI113816 Karlinsky, 1978, Animal models of emphysema, Am. Rev. Respir. Dis., 117, 1099 Karshikov, 1992, Electrostatic interactions in the association of proteins: an analysis of the thrombin-hirudin complex, Protein Sci., 1, 727, 10.1002/pro.5560010605 Kawabata, 1985, Staphylocoagulase-binding region in human prothrombin, J. Biochem., 97, 325, 10.1093/oxfordjournals.jbchem.a135057 Kawaji, 1993, Inhibition of eosinophil peroxidase release by chymotrypsin type protease inhibitors from activated human eosinophils, Arerugi, 42, 1591 Kelly, 1991, Hirudin interruption of heparin-resistant arterial thrombus formation in baboons, Blood, 77, 1006, 10.1182/blood.V77.5.1006.1006 Kline, 1991, Hirulog peptides with scissile bond replacements resistant to thrombin cleavage, Biochem. Biophys. Res. Commun., 177, 1049, 10.1016/0006-291X(91)90644-M Knapp, 1992, Hirudisins: hirudin-derived thrombin inhibitors with disintegrin activity, J. Biol. Chem., 267, 24230, 10.1016/S0021-9258(18)35754-5 Krezel, 1994, Structure of the RGD protein decorsin: conserved motif and dinstinct function in leech proteins that affect blood clotting, Science, 264, 1944, 10.1126/science.8009227 Krstenansky, 1987, Antithrombin properties of C-terminus of hirudin using synthetic unsulfated N-α-acetyl hirudin 45–65, FEBS Lett., 211, 10, 10.1016/0014-5793(87)81264-4 Krstenansky, 1988, Comparison of hirudin and hirudin PA C-terminal fragments and related analogs as antithrombin agents, Thromb. Res., 52, 137, 10.1016/0049-3848(88)90092-8 Krstenansky, 1988, Design, synthesis and antithrombin activity for conformationally restricted analogs of peptide anticoagulants based on the C-terminal region of the leech peptide, hirudin, Biochim. Biophys. Acta, 957, 53, 10.1016/0167-4838(88)90156-2 Krystek, 1993, Affinity and specificity of serine endopeptidase-protein inhibitor interactions: empirical free energy calculations based on X-ray crystallographic structures, J. Mol. Biol., 234, 661, 10.1006/jmbi.1993.1619 Lai, 1990, Inhibition of porcine pancreatic elastase-induced emphysema by eglin c, Exp. Lung. Res., 16, 547, 10.3109/01902149009068826 Laskowski, 1980, Protein inhibitors of proteinases, Annu. Rev. Biochem., 49, 593, 10.1146/annurev.bi.49.070180.003113 Lau, 1990, Proteolytic degradation of human recombinant proinsulin/insulin by sera from acute pancreatitis patients and complete inhibition by eglin c, Pancreas, 5, 17, 10.1097/00006676-199001000-00003 Lau, 1990, Proteolytic degradation of human recombinant proinsulin/insulin by sera from acute pancreatitis patients and complete inhibition by eglin c, Pancreas, 5, 240, 10.1097/00006676-199001000-00003 Lazar, 1991, Hirudin: amino-terminal residues play a major role in the interaction with thrombin, J. Biol. Chem., 266, 685, 10.1016/S0021-9258(17)35224-9 Lidón, 1993, Initial experience with a direct antithrombin, hirulog, in unstable angina: anticoagulant, antithrombotic, and clinical effects, Circulation, 88, 1495, 10.1161/01.CIR.88.4.1495 Lim, 1986, Successful transfer of ‘free’ microvascular superficial temporal artery flap with no obvious venous drainage and use of leeches for reducing venous congestion: case report, Microsurgery, 7, 87, 10.1002/micr.1920070208 Linas, 1992, Mild renal ischemia activates primed neutrophils to cause acute renal failure, Kidney Int., 42, 610, 10.1038/ki.1992.325 Linas, 1991, Role of neutrophil derived oxidants and elastase in lipopolysaccharide-mediated renal injury, Kidney Int., 39, 618, 10.1038/ki.1991.73 Loukusa, 1990, Plasminogen activator is involved in the hCG-induced neutrophil extravasation and vasopermeability increase in the rat testis, Int. J. Androl., 13, 306, 10.1111/j.1365-2605.1990.tb01036.x Lucey, 1986, Effect of varying the time interval between intratracheal administration of eglin c and human neutrophil elastase on prevention of emphysema and secretory cell metaplasia in hamsters: with observations on the fate of eglin c and the effect of repeated instillations, Am. Rev. Respir. Dis., 134, 471 Maier, 1979, Primary structure of yeast proteinase B inhibitor 2, J. Biol. Chem., 254, 12555, 10.1016/S0021-9258(19)86350-0 Major, 1954 Mao, 1987, Rapid purification and revised aminoterminal sequence of hirudin: a specific thrombin inhibitor of the bloodsucking leech, Anal. Biochem., 161, 214, 10.1016/0003-2697(87)90482-9 Marki, 1991, Recombinant hirudin: genetic engineering and structure analysis, Semin. Thromb. Hemost., 17, 88, 10.1055/s-2007-1002594 Markwardt, 1955, Untersuchungen über hirudin, Naturwissenschaften, 42, 537, 10.1007/BF00630151 Markwardt, 1956, Untersuchungen uber den mechanismus der blutgerinnungshemmenden wirkung des hirudins, Arch. Exp. Phatol. Pharmakol., 229, 389, 10.1007/BF00245864 Markwardt, 1957, Die isolierung und chemische characterisierung des hirudins, Hoppe-Seyler's Z. Physiol. Chem., 308, 147, 10.1515/bchm2.1957.308.1.147 Markwardt, 1959, Ueber den einfluß des hirudins auf die thrombenbildung, Arch. Exp. Pathol., 242, 343 Markwardt, 1970, Hirudin as an inhibitor of thrombin, Meth. Enzymol., 19, 924, 10.1016/0076-6879(70)19082-3 Markwardt, 1985, Pharmacology of hirudin: one hundred years after the first report of the anticoagulant agent in medicinal leeches, Biomed. Biochim. Acta, 44, 1007 Markwardt, 1986, Pharmacological approaches to thrombin regulation, Ann. N. Y. Acad. Sci., 485, 204, 10.1111/j.1749-6632.1986.tb34582.x Markwardt, 1988, The comeback of hirudin: an old-established anticoagulant agent, Folia Haematol. Leipz, 115, 10 Markwardt, 1992, Hirudin: the promising antithrombotic, Cardiovasc. Drug Rev., 10, 211, 10.1111/j.1527-3466.1992.tb00247.x Markwardt, 1971, Blutgerinnungshemmende proteine, peptide und aminosäurederivative, Handbook Exp. Pharmacol., 27, 76 Markwardt, 1988, Pharmacological survey of recombinant hirudin, Pharmazie, 43, 202 Markwardt, 1990, Antithrombin effects of native and recombinant hirudins, Biomed. Biochim. Acta, 49, 399 Markwardt, 1982, Pharmacological studies on the antithrombotic action of hirudin in experimental animals, Thromb. Haemost., 47, 226, 10.1055/s-0038-1657173 Markwardt, 1991, Clinical pharmacology of recombinant hirudin, Haemostasis, 21, 133 Markwardt, 1991, Hirudin as anticoagulant in experimental hemodialysis, Haemostasis, 21, 149 Marquart, 1983, The geometry of the reactive site and of the peptide groups in trypsin, trypsinogen and its complexes with inhibitors, Acta Crystallogr., B39, 480, 10.1107/S010876818300275X Maugeri, 1992, Transcellular metabolism of arachidonic acid: increased platelet thromboxane generation in the presence of activated polymorphonuclear leukocytes, Blood, 80, 447, 10.1182/blood.V80.2.447.447 Maywald, 1988, Human pancreatic secretory trypsin inhibitor (PSTI) produced in active form and secreted from Escherichia coli, Gene, 68, 357, 10.1016/0378-1119(88)90038-8 McPhalen, 1987, Crystal and molecular structure of the serine proteinase inhibitor CI-2 from barley seeds, Biochemistry, 26, 261, 10.1021/bi00375a036 McPhalen, 1988, Structural comparison of two serine proteinase-protein inhibitor complexes: eglin c-subtilisin Carlsberg and ci-2-subtilisin Novo, Biochemistry, 27, 6582, 10.1021/bi00417a058 McPhalen, 1985, Crystal and molecular structure of the inhibitor eglin from leeches in complex with subtilisin Carlsberg, FEBS Lett., 188, 55, 10.1016/0014-5793(85)80873-5 McPhalen, 1985, Crystal and molecular structure of chymotrypsin inhibitor 2 from barley seeds in complex with subtilisin Novo, 82, 7242 Menegatti, 1987, Role of the primary specificity subsite on the interaction between serine proteinases and low molecular weight substrates and inhibitors, 101 Menegatti, 1987, Binding of the bovine pancreatic secretory trypsin inhibitor (Kazal) to bovine serine (pro)enzymes, J. Mol. Biol., 198, 129, 10.1016/0022-2836(87)90463-3 Meyer, 1994, Inhibition of growth of thrombus on fresh mural thrombus: targeting optimal therapy, Circulation, 90, 2432, 10.1161/01.CIR.90.5.2432 Meyer, 1994, Local delivery of r-hirudin by a double-balloon perfusion catheter prevents mural thrombosis and minimizes platelet deposition after angioplasty, Circulation, 90, 2474, 10.1161/01.CIR.90.5.2474 Mignatti, 1989, In vitro angiogenesis on the human amniotic membrane: requirement for basic fibroblast growth factor-induced proteinases, J. Cell. Biol., 108, 671, 10.1083/jcb.108.2.671 Morrison, 1990, Inhibition of human leukocyte elastase bound to elastin: relative ineffectiveness and two mechanisms of inhibitory activity, Am. J. Respir. Cell. Mol. Biol., 2, 263, 10.1165/ajrcmb/2.3.263 Mühlhahn, 1994, Structure of leech derived tryptase inhibitor (LDTI-c) in solution, FEBS Lett., 355, 290, 10.1016/0014-5793(94)01225-3 Musil, 1991, Refined X-ray crystal structures of the reactive site modified ovomucoid inhibitor third domains from silver pheasant (OMSVP3∗) and from Japanese quail (OMJPQ3∗), J. Mol. Biol., 220, 739, 10.1016/0022-2836(91)90114-L Naski, 1990, The COOH-terminal domain of hirudin: an exosite-directed competitive inhibitor of the action of α-thrombin on fibrinogen, J. Biol. Chem., 265, 13484, 10.1016/S0021-9258(18)77372-9 Ni, 1990, Thrombin-bound conformation of the C-terminal fragments of hirudin determined by transferred Nuclear Overhauser Effects, Biochemistry, 29, 4479, 10.1021/bi00470a030 1499, Nicander of Colophain, Theriaca et alexipharmaca Nick, 1988, Development of eglin c as a drug: pharmacokinetics, Adv. Exp. Med. Biol., 240, 83, 10.1007/978-1-4613-1057-0_9 Northrup, 1992, Kinetics of protein-protein association explained by Brownian dynamics computer simulation, 89, 3338 Okada, 1990, Synthesis of a heptacontapeptide corresponding to the entire amino acid sequence of eglin c, Chem. Pharm. Bull. Tokyo, 38, 2902, 10.1248/cpb.38.2902 Okada, 1990, Synthesis of a trihexacontapeptide corresponding to the sequence 8–70 of eglin c and studies on the relationship between the structure and the inhibitory activity against human leukocyte elastase, cathepsin G and α-chymotrypsin, FEBS Lett., 272, 113, 10.1016/0014-5793(90)80461-Q Okada, 1989, Synthesis of peptide fragments related to eglin c and examination of their inhibitory effect on human leukocyte elastase, cathepsin G and α-chymotrypsin, Biochem. Biophys. Res. Commun., 161, 272, 10.1016/0006-291X(89)91591-X Olson, 1982, Demonstration of a two-step reaction mechanism for inhibition of α-thrombin by antithrombin III and identification of the step affected by heparin, J. Biol. Chem., 257, 14891, 10.1016/S0021-9258(18)33366-0 Oltersdorf, 1989, The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II, Nature, 341, 144, 10.1038/341144a0 Onesti, 1992, Binding of the Kunitz-type trypsin inhibitor DE-3 from Erythrina caffra seeds to serine proteinases: a comparative study, J. Mol. Recogn., 5, 105, 10.1002/jmr.300050306 Parry, 1994, Kinetic mechanism for the interaction of hirulog with thrombin, Biochemistry, 33, 14807, 10.1021/bi00253a020 Patrignani, 1991, Inactivation of endothelin by polymorphonuclear leukocyte-derived lytic enzymes, Blood, 78, 2715, 10.1182/blood.V78.10.2715.2715 Peng, 1992, Mapping of the spectral densities of NH bond motions in eglin c using heteronuclear relaxation experiments, Biochemistry, 31, 8571, 10.1021/bi00151a027 Pintucci, 1993, Capthepsin G-induced release of PAI-1 in the culture medium of endothelial cells: a new thrombotic role for polymorphonuclear leukocytes?, J. Lab. Clin. Med., 122, 69 Pizzo, 1988, In vivo catabolism of α1-antichymotrypsin is mediated by the serpin receptor which binds α1-proteinase inhibitor, antithrombin iii and heparin cofactor II, Biochim. Biophys. Acta, 967, 158, 10.1016/0304-4165(88)90005-0 Prescott, 1990, Hirudin-based peptides block the inflammatory effects of thrombin on endothelial cells, J. Biol. Chem., 265, 9614, 10.1016/S0021-9258(19)38712-5 Priestle, 1993, Changes in interactions in complexes of hirudin derivatives and human α-thrombin due to different crystal forms, Protein Sci., 2, 1630, 10.1002/pro.5560021009 Qiu, 1992, Structure of the hirulog 3-thrombin complex and nature of the S′ subsites of substrates and inhibitors, Biochemistry, 31, 11689, 10.1021/bi00162a004 Qiu, 1993, Structures of thrombin complexes with a designed and a natural exosite peptide inhibitor, J. Biol. Chem., 268, 20318, 10.1016/S0021-9258(20)80731-5 Quast, 1974, Kinetics of the interaction of bovine pancreatic trypsin inhibitor (Kunitz) with α-chymotrypsin, Biochemistry, 13, 2512, 10.1021/bi00709a600 Quast, 1978, Stopped-flow kinetics of the resynthesis of the reactive site peptide bond in kallikrein inhibitor (Kunitz) by β-trypsin, Biochemistry, 17, 1675, 10.1021/bi00602a015 Rao, 1991, Characterization of proteinase-3 (PR-3), a neutrophil serine proteinase: structural and functional properties, J. Biol. Chem., 266, 9540, 10.1016/S0021-9258(18)92854-1 Read, 1986, Introduction to the protein inhibitors: X-ray crystallography, 301 Renesto, 1991, Tumour necrosis factor-α enhances platelet activation via cathepsin G released from neutrophils, J. Immunol., 146, 2305, 10.4049/jimmunol.146.7.2305 Renesto, 1990, Interference of recombinant eglin c, a proteinase inhibitor extracted from leeches, with neutrophyl-mediated platelet activation, Lab. Invest., 62, 409 Renesto, 1991, Eglin c and heparin inhibition of platelet activation induced by cathepsin G or human neutrophils, Ann. N. Y. Acad. Sci., 624, 321, 10.1111/j.1749-6632.1991.tb17033.x Renesto, 1994, Proteinase 3: a neutrophyl proteinase with activity on platelets, J. Immunol., 152, 4612, 10.4049/jimmunol.152.9.4612 Repine, 1992, Scientific perspective on adult respiratory distress syndrome, Lancet, 339, 466, 10.1016/0140-6736(92)91067-I Ribeiro, 1981, Platelet antiaggregating activity in the salivary secretion of the blood-sucking bug Rhodnius prolixus, Experentia, 37, 384, 10.1007/BF01959876 Ribeiro, 1985, Antihemostatic, antiinflammatory and immunosuppressive properties of the saliva of the tick Ixodes dammini, J. Exp. Med., 161, 332, 10.1084/jem.161.2.332 Richardson, 1974, Chymotryptic inhibitor I from potatoes: the amino acid sequences of subunits B, C and D, FEBS Lett., 45, 11, 10.1016/0014-5793(74)80798-2 Rigbi, 1987, The saliva of the medicinal leech Hirudo medicinalis: 1. biochemical characterization of the high molecular weight fraction, Comp. Biochem. Physiol., 87, 567, 10.1016/0305-0491(87)90053-8 Rigbi, 1987, The Saliva of the Medicinal Leech Hirudo medicinalis: II. Inhibition of platelet aggregation and of leukocyte activity and examination of reputed anaesthetic effects, Comp. Biochem. Physiol., C88, 95 Ringe, 1985, Mapping protein dynamics by X-ray diffraction, Prog. Biophys. Mol. Biol., 45, 197, 10.1016/0079-6107(85)90002-1 Rink, 1984, A large fragment approach to DNA synthesis: total synthesis of a gene for the protease inhibitor eglin c from Hirudo medicinalis and its expression in E.coli, Nucleic Acids Res., 13, 6369, 10.1093/nar/12.16.6369 Rosengren, 1990, Neutrophyl-mediated vascular leakage is not suppressed by leukocyte elastase inhibitors, Am. J. Physiol., 259, H1288 Roters, 1992, Protease inhibitors in the alimentary tract of the medicinal leech Hirudo medicinalis: in vivo and in vitro studies, J. Comp. Physiol., B162, 85 Rydel, 1990, The structure of a complex of recombinant hirudin and human α-thrombin, Science, 249, 277, 10.1126/science.2374926 Rydel, 1991, Refined structure of the hirudin-thrombin complex, J. Mol. Biol., 221, 583, 10.1016/0022-2836(91)80074-5 Scacheri, 1993, Novel hirudin variants from the leech Hirudinaria manillensis: amino acid sequence, cDNA cloning and genomic organization, Eur. J. Biochem., 214, 295, 10.1111/j.1432-1033.1993.tb17924.x Schar, 1988, Modification of recombinant N-α-acetyl-eglin c by novel proteases from Nocardia mediterranei, Ann. N. Y. Acad. Sci., 542, 302, 10.1111/j.1749-6632.1988.tb25847.x Scharf, 1989, Primary structures of new ‘Iso-hirudins’, FEBS Lett., 255, 105, 10.1016/0014-5793(89)81070-1 Schechter, 1967, On the size of the active site in proteases: I. papain, Biochem. Biophys. Res. Commun., 27, 157, 10.1016/S0006-291X(67)80055-X Schleuning, 1990, Complement activation during storage of preserved blood, Beitr. Infusionther., 26, 81 Schleuning, 1992, Complement activation during storage of blood under normal blood bank conditions: effects of proteinase inhibitors and leukocyte depletion, Blood, 79, 3071, 10.1182/blood.V79.11.3071.3071 Schmitt, 1989, Elastase released from human granulocytes stimulated with N-formyl-chemotactic peptide prevents activation of tumour cell prourokinase (pro-uPA), FEBS Lett., 255, 83, 10.1016/0014-5793(89)81065-8 Schmitt, 1991, Human tumour cell urokinase-type plasminogen activator (uPA): degradation of the proenzyme form (pro-uPA) by granulocyte elastase prevents subsequent activation by plasmin, Adv. Exp. Med. Biol., 297, 111, 10.1007/978-1-4899-3629-5_10 Schmitz, 1991, Mechanism of the inhibition of α-thrombin by hirudin-derived fragments hirudin (1–47) and hirudin (45–65), Eur. J. Biochem., 195, 251, 10.1111/j.1432-1033.1991.tb15701.x Schnebli, 1986, Proteinase inhibitors as drugs, 613 Schreuder, 1993, Crystallization and preliminary crystallographic analysis of antistasin, a leech-derived inhibitor of blood coagulation factor Xa, J. Mol. Biol., 231, 1137, 10.1006/jmbi.1993.1360 Schreuder, 1994, Crystal structure of a complex between intact and cleaved human antithrombin III as a model for serpin-proteinase interaction, Nature Struct. Biol., 1, 48, 10.1038/nsb0194-48 Seemüller, 1986, Proteinase inhibitors of the leech Hirudo medicinalis (hirudins, bdellins, eglins), 337 Seemüller, 1977, Isolation and characterization of a low molecular weight inhibitor (of chymotrypsin and human granulocyte elastase and cathepsin G) from leechs, Hoppe-Seyler's Z. Physiol. Chem., 358, 1105, 10.1515/bchm2.1977.358.2.1105 Senior, 1989, Elastin degradation by human alveolar macrophages: a prominent role of metalloproteinase activity, Am. Rev. Respir. Dis., 139, 1251, 10.1164/ajrccm/139.5.1251 Siebeck, 1989, Therapeutic effects of the combination of two proteinase inhibitors in endotoxin shock of the pig, Prog. Clin. Biol. Res., 308, 937 Siebeck, 1992, Effect of the elastase inhibitor eglin c in porcine endotoxin shock, Circ. Shock, 36, 174 Siebeck, 1992, Effects of protease inhibitors in experimental septic shock, Agents Actions Suppl., 38, 421 Skrzypczak-Jankun, 1991, Structure of the hirugen and hirulog 1 complexes of α-thrombin, J. Mol. Biol., 221, 1379, 10.1016/0022-2836(91)90939-4 Smith, 1987, Ozone effects on inhibitors of human neutrophil proteinases, Arch. Biochem. Biophys., 253, 146, 10.1016/0003-9861(87)90647-3 Snider, 1985, Eglin c, a polypeptide derived from the medicinal leech, prevents human neutrophyl elastase-induced emphysema and bronchial secretory cell metaplasia in the hamster, Am. Rev. Respir. Dis., 132, 1155 Söllner, 1994, Isolation and characterization of hirustasin, an antistasin-type serine-proteinase inhibitor from the medical leech Hirudo medicinalis, Eur. J. Biochem., 219, 937, 10.1111/j.1432-1033.1994.tb18575.x Sommerhoff, 1994, A Kazal-type inhibitor of human mast cell tryptase: isolation from the medical leech Hirudo medicinalis, characterization, and sequence analysis, Biol. Chem. Hoppe-Seyler, 375, 685, 10.1515/bchm3.1994.375.10.685 Sponer, 1991, Different susceptibility of elastase inhibitors to inactivation by proteinases from Staphylococcus aureus and Pseudomonas aeruginosa, Biol. Chem. Hoppe-Seyler, 372, 963, 10.1515/bchm3.1991.372.2.963 Stack, 1988, Bronchial leukocyte elastase inhibitor: hydrodynamic properties and interaction with α2-macroglobulin-bound elastase, Arch. Biochem. Biophys., 260, 400, 10.1016/0003-9861(88)90463-8 Starke, 1989, The beginnings of hirudin, TIPS, 10, 99 Steinmeyer, 1991, Influence of some natural and semisynthetic agents on elastase and cathepsin G from polymorphonuclear granulocytes, Arzneimittelforschung, 41, 77 Stone, 1995, Thrombin inhibitors: a new generation of antithrombotics, Trends Cardiovasc. Med., 10.1016/1050-1738(95)00049-F Stone, 1986, Kinetics of the inhibition of thrombin by hirudin, Biochemistry, 25, 4622, 10.1021/bi00364a025 Stone, 1993, Hirudin and hirudin-based peptides, Meth. Enzymol., 223, 312, 10.1016/0076-6879(93)23053-P Stone, 1987, Identification of regions of α-thrombin involved in its interaction with hirudin, Biochemistry, 26, 4617, 10.1021/bi00389a004 Stone, 1989, Quantitative evaluation of the contribution of ionic interactions to the formation of the thrombin-hirudin complex, Biochemistry, 28, 6857, 10.1021/bi00443a012 Stubbs, 1993, A player of many parts: the spotlight falls on thrombin's structure, Thromb. Res., 63, 1, 10.1016/0049-3848(93)90002-6 Stubbs, 1993, Crystal structures of thrombin and thrombin complexes as a framework for antithrombotic drug design, Perspect. Drug Disc. Design, 1, 431, 10.1007/BF02171858 Stubbs, 1994, Coagulation factors and their inhibitors, Curr. Opin. Struct. Biol., 4, 823, 10.1016/0959-440X(94)90263-1 Stubbs, 1995, The structural basis of thrombin inhibition by hirudin and serpins Stubbs, 1995, The clot thickens: clues provided by thrombin structure, TIBS, 20, 23 Suter, 1988, The effect of eglin c on the function of human neutrophils in vitro, Biol. Chem. Hoppe-Seyler, 369, 573, 10.1515/bchm3.1988.369.2.573 Suter, 1986, Levels of free granulocyte elastase in bronchial secretions from patients with cystic fibrosis: effect of antimicrobial treatment against Pseudomonas aeruginosa, J. Infect. Dis., 153, 902, 10.1093/infdis/153.5.902 Suttorp, 1993, Human neutrophil elastase increases permeability of cultured pulmonary endothelial cell monolayers, Int. J. Microcirc. Clin. Exp., 13, 187 Szyperski, 1994, Transient hydrogen bonds identified on the surface of the NMR solution structure of hirudin, Biochemistry, 33, 9303, 10.1021/bi00197a034 Szyperski, 1992, Nuclear magnetic resonance solution structure of hirudin(1–51) and comparison with corresponding three- dimensional structures determined using the complete 65-residue hirudin polypeptide chain, J. Mol. Biol., 228, 1193, 10.1016/0022-2836(92)90325-E Szyperski, 1992, Impact of protein-protein contacts on the conformation of thrombin-bound hirudin studied by comparison with the nuclear magnetic resonance solution structure of hirudin(1–51), J. Mol. Biol., 228, 1206, 10.1016/0022-2836(92)90326-F Tapparelli, 1993, Synthetic low-molecular weight thrombin inhibitors: molecular design and pharmacological profile, TIPS, 14, 366 Teschner, 1988, Eglin c fails to reduce catabolism in acutely uremic rats, Adv. Exp. Med. Biol., 240, 331, 10.1007/978-1-4613-1057-0_39 Tian, 1982, Determination of the rate constant of enzyme modification by measuring the substrate reaction in the presence of the modifier, Biochemistry, 21, 1028, 10.1021/bi00534a031 Totani, 1994, Polymorphonuclear leukocytes enhance release of growth factors by cultured endothelial cells, Arterioscler. Thromb., 14, 125, 10.1161/01.ATV.14.1.125 Travis, 1991, Potential problems in designing elastase inhibitors for therapy, Am. Rev. Respir. Dis., 143, 1412, 10.1164/ajrccm/143.6.1412 Travis, 1983, Human plasma proteinase inhibitors, Annu. Rev. Biochem., 52, 655, 10.1146/annurev.bi.52.070183.003255 Travis, 1985, Isolation and properties of recombinant DNA produced variants of human α1-proteinase inhibitor, J. Biol. Chem., 260, 4384, 10.1016/S0021-9258(18)89276-6 Tripier, 1988, Hirudin: a family of iso-proteins: isolation and sequence determination of new hirudins, Folia Haematol. Leipz., 115, 30 Tsuda, 1994, Design of potent bivalent thrombin inhibitors based on hirudin sequence: incorporation of nonsubstrate-type active site inhibitors, Biochemistry, 33, 14443, 10.1021/bi00252a010 van Obberghen-Schilling, 1982, Hirudin, a probe to analyze the growth-promoting activity of thrombin in fibroblasts: reevaluation of the temporal action of competence factors, Biochem. Biophys. Res. Commun., 106, 79, 10.1016/0006-291X(82)92060-5 Verlinde, 1994, Structure-based drug design: progress, results and challenges, Structure, 2, 577, 10.1016/S0969-2126(00)00060-5 Vijayalakshmi, 1994, The isomorphous structures of prethrombin 2, hirugen- and PPACK-Thrombin: changes accompanying activation and exosite binding to thrombin, Protein Sci., 3, 2254, 10.1002/pro.5560031211 Virca, 1990, Kinetics of association of human proteinases with human α2-macroglobulin, J. Biol. Chem., 259, 8870, 10.1016/S0021-9258(17)47234-6 Virca, 1984, Similarities between human and rat leukocyte elastase and cathepsin G, Eur. J. Biochem., 144, 1, 10.1111/j.1432-1033.1984.tb08423.x Vitali, 1992, The structure of a complex of bovine α-thrombin and recombinant hirudin at 2.8 Å resolution, J. Biol. Chem., 267, 17670, 10.1016/S0021-9258(19)37095-4 von Ritter, 1989, Neutrophilic proteases: mediators of formyl-methionyl-leucyl-phenylalanine-induced ileitis in rats, Gastroenterology, 97, 605, 10.1016/0016-5085(89)90631-8 Wagner, 1992, NMR studies of structure and dynamics of isotope enriched proteins, Biopolymers, 32, 381, 10.1002/bip.360320414 Walenga, 1990, Recombinant hirudin as antithrombotic agent, Drugs Fut., 15, 267 Wallace, 1989, Contribution of the N-terminal region of hirudin to its interaction with thrombin, Biochemistry, 28, 10079, 10.1021/bi00452a030 Wallis, 1988, Hirudins and the role of thrombin: lessons from leechs, TIPS., 9, 425 Wallis, 1989, Inhibition of thrombin, a key step in thrombosis, Drugs Today, 25, 597 Walsmann, 1981, Biochemische und pharmakologische aspekte des trombininhibitors hirudin, Pharmazie, 36, 653 Walsmann, 1989, Biochemical and pharmacological properties of recombinant hirudin, Drugs Today, 25, 473 Weis, 1992, Der Einfluss von r-Hirudin, einem Spezifischen Thrombininhibitor, auf das Akute Lungenversagen im Septischen Schock am Tiermodell Weitz, 1990, Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors, J. Clin. Invest., 86, 385, 10.1172/JCI114723 Wells, 1992, Rapid evolution of peptide and protein binding properties in vitro, Curr. Opin. Struct. Biol., 2, 597, 10.1016/0959-440X(92)90092-L Wells, 1986, Use of binding energy in catalysis analyzed by mutagenesis of the tyrosyl-tRNA synthetase, Biochemistry, 25, 1881, 10.1021/bi00356a007 Wells, 1993, The medical leech: an old treatment revisited, Microsurgery, 14, 183, 10.1002/micr.1920140309 Weng, 1993, Experimentaltherapeutischer Einsatzder Protea seninhibitoren Hirudin und Eglin sowie von Atheplex bei der Endotoxininduzierten Schocklunge des Hausschweines Wewers, 1988, Alveolar fluid neutrophil elastase activity in the acute respiratory distress syndrome is complexed to α2-macroglobulin, J. Clin. Invest., 82, 1260, 10.1172/JCI113724 Wiedow, 1991, Elafin is a potent inhibitor of proteinase 3, Biochem. Biophys. Res. Commun., 174, 6, 10.1016/0006-291X(91)90476-N Wiedow, 1993, Inhibition of proteinase 3 activity by peptides derived from human epidermis, Adv. Exp. Med. Biol., 336, 61, 10.1007/978-1-4757-9182-2_8 Wilcox, 1989, Localization of tissue factor in the normal vessel wall and in the atherosclerotic plaque, 86, 2839 Winant, 1991, Chemical modifications and amino acid substitutions in recombinant hirudin that increase hirudin-thrombin affinity, Biochemistry, 30, 1271, 10.1021/bi00219a016 Witting, 1992, Thrombin-specific inhibition by and slow cleavage of hirulog-1, Biochem. J., 283, 737, 10.1042/bj2830737 Woodman, 1993, Effect of human neutrophil elastase (HNE) on neutrophil function in vitro and in inflamed microvessels, Blood, 82, 2188, 10.1182/blood.V82.7.2188.2188 Yamaguchi, 1991, A membrane-bound metallo-endopeptidase from rat kidney hydrolyzing parathyroid hormone, Eur. J. Biochem., 200, 563, 10.1111/j.1432-1033.1991.tb16219.x Yamamoto, 1993, Effect of leukocyte products on platelet thrombus formation, coagulation and spontaneous thrombolysis, as measured from native human blood, in vitro, Thromb. Res., 71, 281, 10.1016/0049-3848(93)90197-V Zdanov, 1993, Crystal structure of the complex of human α-thrombin and nonhydrolyzable bifunctional inhibitors, hirutonin-2 and hirutonin-6, Proteins, 17, 252, 10.1002/prot.340170304 Zimmerman, 1990, Reperfusion-induced leukocyte infiltration: role of elastase, Am. J. Physiol., 259, H390