Direct thrombin inhibitors – a survey of recent developments

Schwienhorst, Andreas

doi:10.1007/s00018-006-6219-z

Cited by 95 publications

(75 citation statements)

References 195 publications

(212 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…However, no similarities were found in the primary structure of variegin and other thrombin inhibitors. The absence of cysteines, consistent with a flexible structure, also differs from prototypic thrombin inhibitors such as hirudin (compact N terminus, acidic, and extended C terminus) (6,(11)(12)(13), rhodniin (double domain Kazal-type inhibitor) (32,33), ornithodorin (double domain Kunitz-type inhibitor) (34), and theromin (acidic and antistasin-like N terminus, compact C terminus) (35), even though they all bind to the same sites on thrombin (active site and exosite-I) (Fig. 7, A and B).…”

Section: Discussionmentioning

confidence: 93%

“…(PNP: pooled normal plasma; r: r phase, the period of time of latency from the time that blood was placed in the TEG until the initial fibrin formation; k: k phase, a measure of the speed to reach a certain level of clot strength). 6 1D). The anticoagulant activities of these three fractions (AV 3/5, AV 5/5, and AV 6/5) along with crude SGE were verified by PT, APTT, TT, and TEG assays.…”

Section: Resultsmentioning

confidence: 99%

“…Activated protein C (APC) inactivates factor Va and factor VIIIa (FVIIIa), down-regulating the generation of thrombin (1)(2)(3)(4)(5). Thromboembolic disorders are major causes of mortality and morbidity (6). Anticoagulants are pivotal in the prophylaxis and treatment of these disorders.…”

mentioning

confidence: 99%

“…These limitations drive the continual and intense effort to develop new anticoagulants, mainly targeting specific coagulation factors (7). Thrombin represents an ideal target owing to its central role in the coagulation cascade (6,8). Some examples of direct thrombin inhibitors include hirudin, hirulog (or bivalirudin), and agratroban (7)(8)(9).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Variegin, a Novel Fast and Tight Binding Thrombin Inhibitor from the Tropical Bont Tick

Koh

Kazimírová

Trimnell

et al. 2007

Journal of Biological Chemistry

100

101

View full text Add to dashboard Cite

Tick saliva contains potent antihemostatic molecules that help ticks obtain their enormous blood meal during prolonged feeding. We isolated thrombin inhibitors present in the salivary gland extract from partially fed female Amblyomma variegatum, the tropical bont tick, and characterized the most potent, variegin, one of the smallest (32 residues) thrombin inhibitors found in nature. Full-length variegin and two truncated variants were chemically synthesized. Despite its small size and flexible structure, variegin binds thrombin with strong affinity (K i ϳ 10.4 pM) and high specificity. Results using the truncated variants indicated that the seven residues at the N terminus affected the binding kinetics; when removed, the binding characteristics changed from fast to slow. Further, the thrombin active site binding moiety of variegin is in the region of residues 8 -14, and the exosite-I binding moiety is within residues 15-32. Our results show that variegin is structurally and functionally similar to the rationally designed thrombin inhibitor, hirulog. However, compared with hirulog, variegin is a more potent inhibitor, and its inhibitory activity is largely retained after cleavage by thrombin.Blood coagulation is part of the physiological response to vascular injury, in which circulating zymogens of serine proteases are sequentially activated by limited proteolysis leading to the formation of a fibrin clot. Within this network of reactions, thrombin plays a central role in maintaining the integrity of hemostasis. Thrombin interacts with most of the zymogens and their cofactors, playing multiple procoagulant and anticoagulant roles in blood coagulation (1, 2). As a procoagulant protease, the first traces of thrombin generated in the initiation phase activate factor V (FV) 2 and factor VIII (FVIII) to provide positive feedback leading to the thrombin burst. Thrombin can also activate factor XI, triggering the intrinsic pathway. Thrombin cleaves fibrinogen to fibrin, forming insoluble clots. Fibrin polymers are further strengthened and stabilized through covalent cross-linking driven by thrombin-activated factor XIII. Thrombin also contributes to the generation of a platelet plug, possibly through two mechanisms: (a) it activates platelets by interacting with protease-activated receptors and glycoprotein V, and (b) it prevents destabilization of the platelet plug, by inactivating ADAMTS13, a disintegrin and metalloprotease with a thrombospondin type 1 motif, that cleaves von Willebrand factor. As an anticoagulant protease, thrombin activates protein C in the presence of the cofactor thrombomodulin.

show abstract

Section: Discussionmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Variegin, a Novel Fast and Tight Binding Thrombin Inhibitor from the Tropical Bont Tick

Koh

Kazimírová

Trimnell

et al. 2007

Journal of Biological Chemistry

100

101

View full text Add to dashboard Cite

show abstract

“…On the other hand, the US Food and Drug Administration approved human thrombin to be used to help control bleeding during surgery [7]. Thus, it is important and necessary to detect thrombin in blood not only for patients suffering from diseases known to be associated with coagulation abnormalities [8], but also for determining the effectiveness of therapeutic drugs after surgery or in thromboembolic disease treatment [9,10].…”

Section: Introductionmentioning

confidence: 99%

Highly sensitive detection of human thrombin in serum by affinity capillary electrophoresis/laser-induced fluorescence polarization using aptamers as probes

Song

Zhang

et al. 2009

Journal of Chromatography A

View full text Add to dashboard Cite

a b s t r a c tThe detection and quantification of disease-related proteins play critical roles in clinical practice and diagnostic assays. We present an affinity probe capillary electrophoresis/laser-induced fluorescence polarization (APCE/LIFP) assay for detection of human thrombin using a specific aptamer as probe. In the APCE/LIFP assay, the mobility and fluorescence polarization of complex are measured simultaneously during CE analysis. The affinity complex of human thrombin can be well separated from unbound aptamer on CE and clearly identified on the basis of its fluorescence polarization and migration. Because of the binding favorable G-quartet conformation potentially involved in the specific aptamer, it was assumed that monovalent and bivalent cations promoting the formation of a stable G quadruplex conformation in the aptamer may enhance the binding of the aptamer and thrombin. Therefore, we investigated the effects of various metal cations on the binding of human thrombin and the aptamer. Our results show that cations like K + and Mg 2+ could not stabilize the affinity complex. Without the use of typical cations, a highly sensitive assay of human thrombin was developed with the corresponding detection limits of 4.38 × 10 −19 and 2.94 × 10 −19 mol in mass for standard solution and human serum, respectively.

show abstract

Serine Proteases and Serine Protease Inhibitors

Page

2008

Wiley Encyclopedia of Chemical Biology

View full text Add to dashboard Cite

Serine proteases are among the largest group of proteolytic enzymes in the human genome that play vital roles in health and disease. Regulation of their activity in vivo is mediated by a diverse group of serine protease inhibitors. An overview of the interplay between serine proteases and their inhibitors is provided. In addition, approaches to characterize this relationship are discussed with subsequent emphasis on how such measures apply to pathologies that result from defect of serine proteases or their inhibitors.

show abstract

Direct thrombin inhibitors – a survey of recent developments

Cited by 95 publications

References 195 publications

Variegin, a Novel Fast and Tight Binding Thrombin Inhibitor from the Tropical Bont Tick

Variegin, a Novel Fast and Tight Binding Thrombin Inhibitor from the Tropical Bont Tick

Highly sensitive detection of human thrombin in serum by affinity capillary electrophoresis/laser-induced fluorescence polarization using aptamers as probes

Serine Proteases and Serine Protease Inhibitors

Contact Info

Product

Resources

About