Chromogenic substrates as fundamental tool to design new thrombin inhibitors. Determination of inhibition equilibrium constants.

Abstract:

:The structure-activity relationship of dipetalogastin II, the strongest thrombin inhibitor isolated and cloned from the bug Dipetalogaster maximus, was examined by introducing gradual changes into the molecule by means of molecular biological methods. The effect upon its inhibition equilibrium constant was determined after each change by a chromogenic assay. This structural information was fundamental to design new dipetalogastin II-derived inhibitors. Our results suggested that the acidic sequence DEHDHDFEDT corresponding to amino acid residues 49 to 58 of dipetalogastin II reacts with the anion binding exosite (ABE) 1 of thrombin. Based on this finding, we constructed a chimeric molecule consisting of the active site blocking segment of dipetalogastin II (amino acid residues 1 to 48) and the ABE 1 blocking segment of hirudin. This construct showed better thrombin inhibitory activity than both separated segments only after the introduction of a glycine linker between both blocking segments. We thus obtained a thrombin inhibitor called dipetarudin with an inhibition equilibrium constant comparable to that of dipetalogastin II and a molecular mass below that of dipetalogastin.

journal_name

Hamostaseologie

journal_title

Hamostaseologie

authors

Lopez M,Nowak G

doi

10.1267/hämo05030267

keywords:

subject

Has Abstract

pub_date

2005-08-01 00:00:00

pages

267-71

issue

3

eissn

0720-9355

issn

2567-5761

pii

05030267

journal_volume

25

pub_type

杂志文章
  • [Risk assessment of recurrence of venous thromboembolism].

    abstract::Recurrent venous thromboembolism is associated with increased mortality in 5-9% of the patients. On the other hand prolonged anticoagulation can increase the bleeding risk which can also be responsible for an increased mortality. Therefore, it is necessary to validate the recurrence risk of venous thromboembolism on a...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/ha-1144

    authors: Lindhoff-Last E

    更新日期:2011-02-01 00:00:00

  • Oxidation-specific epitopes are major targets of innate immunity in atherothrombosis.

    abstract:UNLABELLED:Atherosclerosis is a chronic inflammatory disease of the vascular wall that results from disturbed lipoprotein metabolism and increased oxidative stress. A major consequence of this is lipid peroxidation, which generates a number of breakdown products of membrane lipids that form so called oxidation-specific...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/HAMO-14-11-0069

    authors: Bartolini Gritti B,Binder CJ

    更新日期:2016-05-10 00:00:00

  • Health Care Transition of Adolescents and Young Adults with Haemophilia: the Situation in Germany and the Munich experience.

    abstract::Patients suffering from haemophilia encounter various phases in life, in which individual needs, life situations, and self- and disease perception change rapidly. One of these phases spans from the beginning of puberty until early adulthood, in which individuals gain self-responsibility and reach independence and auto...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.1055/s-0039-3402804

    authors: Bidlingmaier C,Olivieri M,Schilling FH,Kurnik K,Pekrul I

    更新日期:2020-02-01 00:00:00

  • Platelet monitoring for PCI: is it really necessary?

    abstract::Percutaneous coronary intervention (PCI) has significantly improved clinical outcomes in coronary artery disease patients. Since PCI is associated with platelet activation, antiplatelet therapy with aspirin, clopidogrel and GPIIb/IIIa inhibitors comprise the cornerstone strategy during and following PCI. The latter ag...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:

    authors: Tantry US,Gurbel PA

    更新日期:2009-11-01 00:00:00

  • Trauma-Induced Coagulopathy.

    abstract::Trauma-induced coagulopathy (TIC) is a heterogeneous entity that contributes to a significant morbidity and mortality following trauma. The activated protein C system, endotheliopathy and platelet dysfunction have been implicated in the pathogenesis of TIC, although there are still controversies on the exact pathogene...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.1055/s-0039-1677853

    authors: Petros S

    更新日期:2019-02-01 00:00:00

  • Hermansky-Pudlak syndrome. Overview of clinical and molecular features and case report of a new HPS-1 variant.

    abstract::Hermansky-Pudlak syndrome (HPS) is a rare, autosomal recessive disorder affecting lysosome-related organelles (LRO), including dense platelet granules. HPS causes oculocutaneous hypopigmentation, bleeding diathesis and granulomatous colitis or pulmonary fibrosis. To date, there is no curative treatment and the clinica...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/HAMO-14-06-0024

    authors: Sánchez-Guiu I,Torregrosa JM,Velasco F,Antón AI,Lozano ML,Vicente V,Rivera J

    更新日期:2014-01-01 00:00:00

  • Arterial thrombus formation. Novel mechanisms and targets.

    abstract::Platelet and coagulation factor-dependent thrombus formation is critical to limit posttraumatic blood loss at sites of vascular injury. However, under pathological conditions like rupture of an atherosclerotic plaque, it may also lead to vessel occlusion causing myocardial infarction or stroke. Therefore, antithrombot...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:

    authors: Hagedorn I,Vögtle T,Nieswandt B

    更新日期:2010-08-01 00:00:00

  • [Antithrombotic therapy of acute coronary syndromes].

    abstract::Recent advances in the diagnosis and the treatment of acute coronary syndromes (ACS) have led to a substantial reduction of major coronary events, to an improvement in patient outcome and the definition of new guidelines. Current strategies for the treatment of patients with non-ST-elevation ACS recommend a combined a...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:

    authors: Hölschermann H

    更新日期:2007-12-01 00:00:00

  • Old and new anticoagulants.

    abstract::Vitamin-K-antagonists (VKA) and heparins have been complementary anticoagulants for prevention and treatment of thrombosis for almost 70 years. In contrast to heparins, VKA have not been modified pharmacologically, however treatment surveillance has improved by introducing INR and self-monitoring/management. Disclosur...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/ha-1149

    authors: Harbrecht U

    更新日期:2011-02-01 00:00:00

  • Use of recombinant factor VIIa in the perioperative period.

    abstract::Recombinant activated factor VII (rFVIIa) is a pro-haemostatic agent that can be used for patients with haemophilia and inhibiting antibodies towards a coagulation factor. Recombinant factor VIIa is, however, increasingly used for several other indications, including patients who experience serious and life-threatenin...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:

    authors: Levi M

    更新日期:2009-01-01 00:00:00

  • Follow-up of a 6-month Programmed Sports Therapy (PST) in patients with haemophilia.

    abstract::Studies describe benefits of exercise in Patients with haemophilia (PwH), but research on training sustainability is rare. Aim of this study was to observe the follow-up of a guided 6-month training intervention in PwH. This study included 28 PwH after a training intervention (RCT) over 6 months. N=17 continued traini...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,随机对照试验

    doi:10.5482/HAMO-17-04-0016

    authors: Runkel B,Hilberg T

    更新日期:2017-01-01 00:00:00

  • Acquired Haemophilia A Associated with Subsequent Hepatocellular Carcinoma.

    abstract::Acquired haemophilia A (AHA) is a rare autoimmune disease caused by antibodies directed against clotting factor VIII. About half of cases are idiopathic, but AHA may also be secondary to autoimmune, dermatologic, or oncologic diseases. In approximately 10% of non-idiopathic cases, the disease occurs after or with the ...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:10.1055/s-0038-1668570

    authors: Pacholczak R,Bazan-Socha S,Zdziarska J,Iwaniec T,Walocha JA,Musiał J,Dropiński J

    更新日期:2019-02-01 00:00:00

  • DOAC use in patients with chronic kidney disease.

    abstract::Direct oral anticoagulants (DOACs) are increasingly prescribed substances in patients with indication for effective anticoagulation. Patients with chronic kidney disease (CKD) have a high burden of cardiovascular risk and are more likely to develop atrial fibrillation (AF) than patients without CKD. Patients with mild...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/HAMO-17-01-0003

    authors: Kcükköylü S,Rump LC

    更新日期:2017-01-01 00:00:00

  • Nucleic acid aptamers and their complimentary antidotes. Entering an era of antithrombotic pharmacobiologic therapy.

    abstract::The translation of fundamental science-based constructs to the preemptive identification and optimal management of individuals with or those at risk for thrombotic disorders of the cardiovascular system has taken a step closer to being realized with the development of molecular technologies that include nucleic acid a...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:

    authors: Becker RC,Oney S,Becker KC,Rusconi CP,Sullenger B

    更新日期:2007-12-01 00:00:00

  • Child Abuse or Bleeding Disorder-An Interdisciplinary Approach.

    abstract::Children with an unexplained bleeding tendency are frequently referred to a haemostaseologist for further evaluation. Careful standardized history taking and clinical evaluation should allow for distinguishing bleeds after minor injury and trauma which are very common in all children. However, in two groups of childre...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.1055/s-0039-1677714

    authors: Knöfler R,Streif W,Watzer-Herberth I,Hahn G,Schmidt U

    更新日期:2019-02-01 00:00:00

  • Complement activation in thrombotic microangiopathy.

    abstract::The endothelium lining the vascular lumen is continuously exposed to complement from the circulation. When erroneously activated on host cells, complement may generate a deleterious effect on the vascular wall leading to endothelial injury, exposure of the subendothelial matrix and platelet activation. In this review ...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/HAMO-12-12-0025

    authors: Karpman D,Tati R

    更新日期:2013-05-29 00:00:00

  • [Laboratory diagnosis of the lupus anticoagulants].

    abstract::The antiphospholipid syndrome is defined as the occurrence of one or more episodes of vascular thrombosis and/or miscarriage together with antiphospholipid antibodies. Some of these antibodies can be detected via coagulation assays by prolonging phospholipids-dependent assays. These unspecific inhibitors are termed lu...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.1267/hämo05010050

    authors: Quehenberger P,Wagner O

    更新日期:2005-02-01 00:00:00

  • Thrombophilia and its impact on pregnancy.

    abstract:UNLABELLED:In recent years thrombophilia has gained much attention as a risk factor for pregnancy complications. Whereas there is an established correlation between antiphospholipid-antibodies and pregnancy loss, data for other risk factors of thrombosis are less well established. Data suggest associations with antithr...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:

    authors: Pabinger I

    更新日期:2008-01-01 00:00:00

  • Anticoagulation during and after acute coronary syndrome.

    abstract::Current antithrombotic therapy in patients with acute coronary syndrome (ACS) comprises antiplatelet and anticoagulant therapy. Dual antiplatelet therapy composed of aspirin plus a third generation P2Y12 inhibitor (prasugrel or ticagrelor) represents the gold standard, while aspirin plus second generation P2Y12 inhibi...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/HAMO-13-09-0048

    authors: Ahrens I,Bode C,Zirlik A

    更新日期:2014-01-01 00:00:00

  • Cofactor-Independent Antiphospholipid Antibodies: Implications for Pathogenesis, Diagnosis, and Treatment of Antiphospholipid Syndrome.

    abstract::The antiphospholipid syndrome (APS) has occupied haemostaseologists, rheumatologists and obstetricians since its initial description 35 years ago. Its name has been coined because of the antibodies against phospholipids which were the common property of affected patients. In particular, the pathogenesis of APS has bee...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.1055/s-0038-1675355

    authors: Lackner KJ,Müller-Calleja N

    更新日期:2019-06-01 00:00:00

  • The vulnerable blood.

    abstract::Patients with diabetes are at increased risk of cardiovascular morbidity and mortality. While arteriosclerotic lesions have long been recognized as the underlying cause more recent studies suggest that alterations of the blood are also critically involved. Following plaque rupture, adherence of platelets is followed b...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:10.5482/HAMO-14-09-0039

    authors: Hess K

    更新日期:2015-01-01 00:00:00

  • Mouse models to study von Willebrand factor structure-function relationships in vivo.

    abstract::Von Willebrand factor (VWF) structure-function relationship has been studied only through in vitro approaches. The VWF-deficient mouse model has been extremely useful to examine the in vivo function of VWF but does not allow a more subtle analysis of the relative importance of its different domains. However, consideri...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:

    authors: Denis CV,Marx I,Badirou I,Pendu R,Christophe O

    更新日期:2009-01-01 00:00:00

  • [Inhibitor development after changing FVIII/IX products in patients with haemophilia].

    abstract:UNLABELLED:The retrospective observational study surveys the relationship between development of inhibitors in the treatment of haemophilia patients and risk factors such as changing FVIII products. A total of 119 patients were included in this study, 198 changes of FVIII products were evaluated. RESULTS:During the ob...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:

    authors: Kocher S,Asmelash G,Makki V,Müller S,Krekeler S,Alesci S,Miesbach W

    更新日期:2012-01-01 00:00:00

  • Analysis of an Inherited Dysfibrinogenemia Pedigree Associated with a Heterozygous Mutation in the FGA Gene.

    abstract:OBJECTIVE: This article aims to analyze the phenotype and genotype of an inherited dysfibrinogenemia pedigree associated with a heterozygous mutation in the FGA gene, and to investigate the pathogenesis of this disease. CLINICAL PRESENTATION: The proband of interest is a 29-year-old woman. She was in her 37 weeks of g...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:10.1055/a-1261-3884

    authors: Li S,Wang M,Li X,Xu Q,Liu S,Luo S,Chen Y

    更新日期:2020-12-01 00:00:00

  • The Impact of Bleeding Disorders on the Socioeconomic Status of Adult Patients.

    abstract::The impact of inherited bleeding disorders on the socioeconomic status (SES) of affected individuals is not clear. The SES of adult patients with congenital bleeding disorders (PWBD) from a centre in Germany (age 42.3 ± 15.0 years) was compared to that of a gender- and age-matched control group of patients with thromb...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:10.5482/HAMO-16-12-0047

    authors: Holstein K,von Mackensen S,Bokemeyer C,Langer F

    更新日期:2018-08-01 00:00:00

  • Methylation analysis of the promoter region and intron 1 of the factor VIII gene in haemophilia A patients.

    abstract::Methylation, CpG island, promoter, intron 1 Haemophilia A is the most common X-linked inherited coagulation disorder caused by a deficiency of the factor VIII protein (FVIII). A plethora of different mutations in the factor VIII gene (F8) have been identified as causative for this bleeding disease including a few prom...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:

    authors: Zimmermann MA,Hansmann T,Haaf T,Oldenburg J,Müller CR,Rost S

    更新日期:2013-01-01 00:00:00

  • IWR-1 Inhibits Collagen-Induced Platelet Activation and Protects against Thrombogenesis.

    abstract::Platelets play a crucial role in haemostasis and several pathophysiological processes. Collagen is a main initiator for platelet activation and aggregation. Given that Wnt signalling negatively regulates platelet function, and IWR-1 (a small molecule inhibitor for Wnt signalling) has the potential of inhibiting collag...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:10.1055/s-0038-1676822

    authors: Wang W,Lai S,Xiao Z,Yan H,Li Y,Zhang Y,Wu Y,Wang L

    更新日期:2019-11-01 00:00:00

  • MRI, the technology for imaging of thrombi and inflammation.

    abstract::Atherosclerosis and its sequelae have a major impact on morbidity and mortality. The rupture of an inflamed atherosclerotic plaque is a crucial event, since it can result in acute thrombotic closure of an arterial vessel, resulting e. g. in myocardial infarction or stroke. Not only detection of early plaque rupture wi...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/HAMO-14-11-0061

    authors: von Zur Muhlen C,Bode C

    更新日期:2015-01-01 00:00:00

  • Thrombin generation and venous thromboembolism.

    abstract::Venous thromboembolism is a chronic and potential fatal disease. Determination of recurrence risk is time-consuming and costly, and sometimes not feasible: many patients carry more than one risk factor, the relevance of some factors with regard to risk of recurrence is unknown, and existence of thus far unknown risk f...

    journal_title:Hamostaseologie

    pub_type: 杂志文章

    doi:

    authors: Eichinger S

    更新日期:2008-02-01 00:00:00

  • The role of the kynurenine pathway of tryptophan metabolism in cardiovascular disease. An emerging field.

    abstract::Coronary heart disease and stroke, the deadliest forms of cardiovascular disease (CVD), are mainly caused by atherosclerosis, a chronic inflammatory disease of the artery wall driven by maladaptive immune responses in the vessel wall. Various risk factors for CVD influence this pathogenic process, including diabetes m...

    journal_title:Hamostaseologie

    pub_type: 杂志文章,评审

    doi:10.5482/HAMO-14-10-0052

    authors: Polyzos KA,Ketelhuth DF

    更新日期:2015-01-01 00:00:00