Last update 01 Nov 2024

Serine protease x KLKB1 x Plasmin

Last update 01 Nov 2024

Basic Info

Related Targets

Serine proteaseKLKB1Plasmin

Drugs associated with Serine protease x KLKB1 x Plasmin

BCX-1470

Target

KLKB1 x Plasmin x Serine protease

Mechanism

KLKB1 inhibitors [+2]

Active Org.-

Originator Org.

BioCryst Pharmaceuticals, Inc.

Active Indication-

Inactive Indication

Blood Coagulation Disorders [+1]

Drug Highest PhaseDiscontinued

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with Serine protease x KLKB1 x Plasmin

100 Translational Medicine associated with Serine protease x KLKB1 x Plasmin

0 Patents (Medical) associated with Serine protease x KLKB1 x Plasmin

Literatures (Medical) associated with Serine protease x KLKB1 x Plasmin

01 Sep 2023·The American Journal of Pathology

Increased Matrix Metalloproteinase-1 Activation Enhances Disruption and Regression of k-RasV12–Expressing Arteriovenous Malformation-Like Vessels

Article

Author: Yrigoin, Ksenia ; Davis, George E ; Lin, Prisca K ; Kemp, Scott S ; Sun, Zheying

This study sought to identify potential mechanisms by which k-RasV12-expressing endothelial cell (EC) tubes demonstrate an increased propensity to regress compared with controls. Activated k-Ras mutations play a role in a variety of pathological conditions, including arteriovenous malformations, which are prone to bleed, causing serious hemorrhagic complications. ECs expressing active k-RasV12 demonstrate markedly excessive lumen formation with widened and shortened tubes accompanied by reduced pericyte recruitment and basement membrane deposition, leading to deficient capillary network assembly. The current study showed that active k-Ras-expressing ECs secreted greater amounts of MMP-1 proenzyme compared with control ECs, and readily converted it to increased active MMP-1 levels through the action of plasmin or plasma kallikrein (generated from their added zymogens). Active MMP-1 degraded three-dimensional collagen matrices, leading to more rapid and extensive regression of the active k-Ras-expressing EC tubes, in conjunction with matrix contraction, compared with control ECs. Under conditions where pericytes protect control EC tubes from plasminogen- and MMP-1-dependent tube regression, this failed to occur with k-RasV12 ECs, due to reduced pericyte interactions. In summary, k-RasV12-expressing EC vessels showed an increased propensity to regress in response to serine proteinases through accentuated levels of active MMP-1, a novel pathogenic mechanism that may underlie hemorrhagic events associated with arteriovenous malformation lesions.

01 Feb 2011·Journal of Biological ChemistryQ2 · BIOLOGY

Engineering Kunitz Domain 1 (KD1) of Human Tissue Factor Pathway Inhibitor-2 to Selectively Inhibit Fibrinolysis

Q2 · BIOLOGY

Article

Author: Yogesh Kumar ; Amy E. Schmidt ; Godwin I. Ogueli ; Madhu S. Bajaj ; Sreejesh Shanker ; Gregory Lawson ; Kanagasabai Vadivel ; S. Paul Bajaj

Tissue factor pathway inhibitor-2 (TFPI-2) inhibits factor XIa, plasma kallikrein, and factor VIIa/tissue factor; accordingly, it has been proposed for use as an anticoagulant. Full-length TFPI-2 or its isolated first Kunitz domain (KD1) also inhibits plasmin; therefore, it has been proposed for use as an antifibrinolytic agent. However, the anticoagulant properties of TFPI-2 or KD1 would diminish its antifibrinolytic function. In this study, structure-based investigations and analysis of the serine protease profiles revealed that coagulation enzymes prefer a hydrophobic residue at the P2' position in their substrates/inhibitors, whereas plasmin prefers a positively charged arginine residue at the corresponding position in its substrates/inhibitors. Based upon this observation, we changed the P2' residue Leu-17 in KD1 to Arg (KD1-L17R) and compared its inhibitory properties with wild-type KD1 (KD1-WT). Both WT and KD1-L17R were expressed in Escherichia coli, folded, and purified to homogeneity. N-terminal sequences and mass spectra confirmed proper expression of KD1-WT and KD1-L17R. Compared with KD1-WT, the KD1-L17R did not inhibit factor XIa, plasma kallikrein, or factor VIIa/tissue factor. Furthermore, KD1-L17R inhibited plasmin with ∼6-fold increased affinity and effectively prevented plasma clot fibrinolysis induced by tissue plasminogen activator. Similarly, in a mouse liver laceration bleeding model, KD1-L17R was ∼8-fold more effective than KD1-WT in preventing blood loss. Importantly, in this bleeding model, KD1-L17R was equally or more effective than aprotinin or tranexamic acid, which have been used as antifibrinolytic agents to prevent blood loss during major surgery/trauma. Furthermore, as compared with aprotinin, renal toxicity was not observed with KD1-L17R.

01 Jun 2010·Journal of Thrombosis and HaemostasisQ2 · MEDICINE

Activation of single‐chain urokinase‐type plasminogen activator by platelet‐associated plasminogen: a mechanism for stimulation of fibrinolysis by platelets

Q2 · MEDICINE

Article

Author: J L Degen ; S M Kanse ; N A Booth ; K M Baeten ; M C Richard ; Nicola Jane Mutch

BACKGROUND AND OBJECTIVEPlatelets are essential for hemostasis, and they cause resistance to fibrinolysis by tissue-type plasminogen activator. In contrast, platelets enhance fibrinolysis mediated by single-chain urokinase-type plasminogen activator (scu-PA). This study investigated the mechanism behind this profibrinolytic role of platelets.METHODS AND RESULTSPlatelets enhanced scu-PA activity, but not urokinase-type plasminogen activator (u-PA) activity, in plasma clot lysis and chromogenic assays. We established, using the non-cleavable scu-PA mutant (Lys158-->Glu) and protease inhibitors, that platelets increased activation to u-PA by a serine protease. Activation of scu-PA was platelet-dependent, even in plasma. It occurred in platelet-rich but not in platelet-poor plasma, as assessed by sodium dodecylsulfate polyacrylamide gel electrophoresis and zymography after addition of plasminogen activator inhibitor-1. Candidate proteases that are known to activate scu-PA and are present in platelet preparations were investigated. Factor VII activating protease was detected in platelet preparations by western blotting, but its inhibition by antibodies did not inhibit activation of scu-PA by platelets. Plasmin and plasma kallikrein both mimicked the platelet effect, but were distinguished by their responses to a range of inhibitors. Analysis of platelet-associated protease activity and the time course of scu-PA activation pointed towards plasminogen, and the data were consistent with a mechanism of reciprocal activation. The essential role of plasminogen was revealed using platelets from plasminogen-deficient mice, which could not activate scu-PA. Local plasminogen on platelet membranes was markedly more effective than solution-phase plasminogen in activation of scu-PA.CONCLUSIONSPlatelets enhance fibrinolysis by scu-PA through reciprocal activation of scu-PA and platelet-associated plasminogen, a system that is potentially important in the lysis of platelet-rich thrombi.

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