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Document V. Inactivated Thrombin as an Inhibitor of Clot Formation Page 261 A means to selectively inhibit thrombin's role in coagulation while preserving its anticoagulant functions involves site-directed mutagenesis of thrombin itself. By introduction of a single mutation, Gibbs et al. [29] altered thrombin's relative specificity for fibrinogen and protein C. The engineered thrombin's increased activation of protein C over fibrinogen cleavage offers the possibility of inhibiting clot formation with a modified human protein, a molecule likely to exhibit few side effects. VI. The Role of Structural Information The discovery of thrombin inhibitors has benefited from available protein structural information. Models of the thrombin overall structure and its active site geometry, constructed from available structures of related serine proteases [30], aided in the design of the mechanism-based inhibitors such as PPACK [31] and its boroarginine analog [10]. The unexpected, nonsubstrate binding mode of early thrombin inhibitors such as NAPAP was revealed by x-ray crystallographic analyses [32]. Iterative structurebased design methods have been critical in the optimization of bivalent inhibitors and inhibitors directed at the primary specificity pocket. Structures of inhibitor:thrombin complexes are essential for the optimization of substitutents forming interactions within the aryl-binding site of the primary specificity pocket. In some cases (e.g. Table 1), seemingly minor alterations of the inhibitor can result in dramatic changes in the inhibitor's overall interactions with thrombin [17]. Drug discovery efforts have also been strongly influenced by results of structural studies of thrombin complexed with effectors and substrate peptides. For example, recently the structures of thrombin complexed with fibrinopeptide A [33] and human prothrombin fragment F1 [34] have been determined. In addition to their role in design of high-affinity inhibitors, these structures provide valuable insights for design of drugs specific for the various subsites and conformational states of thrombin. VII. Conclusion Discovery of therapeutically effective thrombin inhibitors involves issues such as affinity and selectivity, bioavailability, and formulation. In addition to these relatively common concerns, the complex in vivo mechanisms designed to http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_261.html [4/5/2004 5:11:30 PM]
Document balance its pro- and anticoagulant activities present additional challenges in the discovery of therapeutically effective thrombin inhibitors. References 1. Tapparelli C, Metternich R, Ehrhardt C, Cook NS. Synthetic low-molecular weight thrombin inhibitors: molecular design and pharmacological profile. TIPS 1993; 14:366–376. 2. Stubbs MT, Bode W. Structure and specificity in coagulation and its inhibition. Trends Cardiovasc Med 1995; 5:157–166. Page 262 3. Stone SR. Thrombin Inhibitors: A new generation of antithrombotics. Trends Cardiovasc. Med. 1995; 5:134–140. 4. Harker LA. Strategies for inhibiting the effects of thrombin. Blood Coagulation and Fibrinolysis 1994; 5:47–58. 5. Claeson G. Synthetic peptides and peptidomimetics as substrates and inhibitors of thrombin and other proteases in the blood coagulation system. Blood Coagulation and Fibrinolysis 1994; 5:411–436. 6. Bode W, Mayr I, Baumann U, Huber R, Stone SR, Hofsteenge J. The refined 1.9 Å crystal structure of human α-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr- Pro-Pro-Trp insertion segment. EMBO J. 1989; 8:3467–3475. 7. Bode W, Turk D, Karshikov A. The refined 1.9-Å X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human α-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Science 1992; 1:426–471. 8. Stubbs MT, Bode W. A Player of many parts: the spotlight falls on thrombin's structure. Thrombosis Research. Vol. 69. Pergamon Press, 1993; 1–58. 9. Whinna HC, Church FC. Interaction of thrombin with antithrombin, heparin cofactor II and protein C inhibitor. Journal of Protein Chemistry 1993; 12:677–688. 10. Weber PC, Lee S-L, Lewandowski FA, Schadt MC, Chang C“ H, Kettner C. Kinetic and crystallographic studies of thrombin with Ac-(D)Phe-Pro-boroArg-OH and its lysine, amidine, homolysine and ornithine analogs. Biochemistry 1995; 34:3750–3757. 11. Deadman JJ, Elgendy S, Goodwin C, Green D, Baban J, Patel G, Skordalakes E, Chino N, Claeson G, Kakkar V, Scully M. Characterization of a class of peptide boronates with neutral P1 side chains as highly selective inhibitors of thrombin. J Med Chem 1995; 38:1511–1522. http://legacy.netlibrary.com/nlreader/nlReader.dll?bookid=12640&filename=Page_262.html (1 of 2) [4/5/2004 5:11:34 PM]
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