Highly active and selective anticoagulants: D-Phe-Pro-Arg-H, a free tripeptide aldehyde prone to spontaneous inactivation, and its stable N-methyl derivative, D-MePhe-Pro-Arg-H

Bajusz, S.; Széll, E.; Bagdy, D; Barabás, Éva; Horváth, Gyula; Dioszegi, Marianne; Fittler, Zsuzsa; Szabó, Gabriella; Juhász, Attila

doi:10.1021/jm00168a030

Cited by 178 publications

(81 citation statements)

References 9 publications

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“…(ii) the electrophilic inhibitors (covalently bound) derived from the tripeptide motif (D)-Phe-Pro-Arg, 17 with the peptide arginal Efegatran 18 and the chloromethylene ketone PPACK, 19 as leads. The only two synthetic thrombin inhibitors, Argatroban 20 and Ximelagatran, 21 available at the moment in the market for the treatment of coagulation complications were developed from the first class of inhibitors.…”

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confidence: 99%

Design, synthesis and evaluation of graftable thrombin inhibitors for the preparation of blood-compatible polymer materials

et al. 2005

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Piperazinyl-amide derivatives of N-a-(3-trifluoromethyl-benzenesulfonyl)-L-arginine(1) were synthesized as graftable thrombin inhibitors. The possible disturbance of biological activity due to a variable spacer-arm fixed on the N-4 piperazinyl position was evaluated in vitro, against human a-thrombin, and in blood coagulation assay. Molecular modelling (in silico analysis) and X-ray diffraction studies of thrombin-inhibitor complexes were also performed. The fixation of bioactive molecules on poly(butylene terephthalate) (PBT) and poly(ethylene terephthalate) (PET) membranes was performed by wet chemistry treatment and evaluated by XPS analysis. Surface grafting of inhibitor 1d improved the membrane hemocompatibility by reducing blood clot formation on the modified surface.

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confidence: 99%

Design, synthesis and evaluation of graftable thrombin inhibitors for the preparation of blood-compatible polymer materials

et al. 2005

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“…1). To find antithrombotic drugs, many inhibitors of thrombin have been developed (2)(3)(4)(5). But factor Xa, which is also essential for both the intrinsic and extrinsic pathways of the coagulation process, is thought to be a better target of antithrombotic drugs because many thrombin inhibitors have been shown to increase the risk of abnormal bleeding (6)(7)(8).…”

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confidence: 99%

Structural basis for chemical inhibition of human blood coagulation factor Xa

Kamata

Kawamoto

Honma

et al. 1998

Proc. Natl. Acad. Sci. U.S.A.

129

110

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Factor Xa, the converting enzyme of prothrombin to thrombin, has emerged as an alternative (to thrombin) target for drug discovery for thromboembolic diseases. An inhibitor has been synthesized and the crystal structure of the complex between Des[1-44] factor Xa and the inhibitor has been determined by crystallographic methods in two different crystal forms to 2.3-and 2.4-Å resolution. The racemic mixture of inhibitor FX-2212, (2RS)-(3-amidino-3-biphenylyl)-5-(4-pyridylamino)pentanoic acid, inhibits factor Xa activity by 50% at 272 nM in vitro. The S-isomer of FX-2212 (FX-2212a) was found to bind to the active site of factor Xa in both crystal forms. The biphenylamidine of FX-2212a occupies the S1-pocket, and the pyridine ring makes hydrophobic interactions with the factor Xa aryl-binding site. Several water molecules meditate inhibitor binding to residues in the active site. In contrast to the earlier crystal structures of factor Xa, such as those of apo-Des[1-45] factor Xa and Des[1-44] factor Xa in complex with a naphthyl inhibitor DX-9065a, two epidermal growth factor-like domains of factor Xa are well ordered in both our crystal forms as well as the region between the two domains, which recently was found to be the binding site of the effector cell protease receptor-1. This structure provides a basis for designing next generation inhibitors of factor Xa.Thromboembolic disease is caused by the improper functioning of the blood coagulation process. Blood clots are formed by a zymogen activation cascade of serine proteases, and the last protease of the cascade, thrombin, converts fibrinogen to fibrin, which cross-links to form blood clots (for a review, see ref.

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“…la) with the hydroxyl group of Ser'95, part of the thrombin catalytic triad His57-Asp102-Ser'95 [chymotrypsinogen numbering (11,12)], to generate a tetrahedral intermediate (13)(14)(15). Also, CtA contains a Pro-Arg structural motif that correlates with the P2-P1 positions in the tripeptide class of thrombin inhibitors, represented by D-Phe-Pro-Arg-CH2Cl (PPACK) (16,17) and Me-D-Phe-Pro-Arg-H (GYKI-14766) (18,19) (Fig. lb).…”

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confidence: 99%

Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A.

Maryanoff

Qiu

Padmanabhan

et al. 1993

Proc. Natl. Acad. Sci. U.S.A.

108

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The macrocyclic peptide cyclotheonamide A (CtA), isolated from the marine sponge Theonella sp., represents an unusual class of serine protease inhibitor. A complex of this inhibitor with human a-thrombin, a protease central to the bioregulation of thrombosis and hemostasis, was studied by x-ray crystallography. This work (2.3-A resolution) confirms the structure of CtA and reveals intimate details about its molecular recognition within the enzyme active site. Interactions due to the "Pro-Arg motif" (Arg occupancy of the SI specificity pocket; formation of a hydrogen-bonded two-strand antiparallel 3-sheet with Ser214-Gly216) and the a-keto amide group of CtA are primarily responsible for binding to thrombin, with the a-keto amide serving as a transition-state analogue. A special interaction with the "insertion loop" of thrombin (Tyr6OA-Thr60I) is manifested through engagement of the hydroxyphenyl group of CtA with Trp6OD as part of an "aromatic stacking chain." Biochemical inhibition data (K, values at 37C) were obtained for CtA with thrombin and a diverse collection of serine proteases. Thus, CtA is just a moderate inhibitor of human ae-thrombin (K, = 0.18 ,IM) but a potent inhibitor of trypsin (Kj = 0.023 IAM) and streptokinase (K, = 0.035 ,AM). The relative lack of potency of CtA as a thrombin inhibitor is discussed with respect to certain structural features of the enzyme complex. We also report the total synthesis of CtA, by a convergent [2 + 3] fragmentcondensation approach, to serve the preparation of cyclotheonamide analogues for structure-function studies.

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Highly active and selective anticoagulants: D-Phe-Pro-Arg-H, a free tripeptide aldehyde prone to spontaneous inactivation, and its stable N-methyl derivative, D-MePhe-Pro-Arg-H

Cited by 178 publications

References 9 publications

Design, synthesis and evaluation of graftable thrombin inhibitors for the preparation of blood-compatible polymer materials

Design, synthesis and evaluation of graftable thrombin inhibitors for the preparation of blood-compatible polymer materials

Structural basis for chemical inhibition of human blood coagulation factor Xa

Molecular basis for the inhibition of human alpha-thrombin by the macrocyclic peptide cyclotheonamide A.

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