Textilinin‐1, an alternative anti‐bleeding agent to aprotinin: Importance of plasmin inhibition in controlling blood loss

Flight, Simone; Johnson, Lambro A.; Du, Qianyun; Warner, Roscoe L.; Trabi, Manuela; Gaffney, Patrick J.; Lavin, Martin F.; Jersey, John de; Masci, Paul P.

doi:10.1111/j.1365-2141.2009.07605.x

Cited by 47 publications

(38 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…36 Tail bleeding times have typically been used to provide a measure of hemostasis in vivo, and tail bleeding times in mice are sensitive to both alterations in coagulation 37 or fibrinolysis. 38 Our observation that bleeding time is reduced in S100A10 Ϫ/Ϫ mice, compared with WT mice, is consistent with the decreased fibrinolysis exhibited by the S100A10 Ϫ/Ϫ mice. Bleeding time has been shown to be significantly increased in the Pg Ϫ/Ϫ mice compared with WT mice, 39 whereas another group found no To detect the total cellular levels of annexin A2 and S100A10, primary murine endothelial cells, isolated from WT or S100A10 Ϫ/Ϫ mice (A), as well as control and S100A10 depleted TIME cells (B), were dissociated from culture flasks, lysed, subjected to SDS-PAGE, and immunoblotted with antiactin (loading control), antiannexin A2, or anti-S100A10 antibodies.…”

Section: S100a10 and Fibrinolysis 3177supporting

confidence: 85%

Regulation of fibrinolysis by S100A10 in vivo

Surette

Madureira

Phipps

et al. 2011

Blood

111

View full text Add to dashboard Cite

Endothelial cells form the inner lining of vascular networks and maintain blood fluidity by inhibiting blood coagulation and promoting blood clot dissolution (fibrinolysis). Plasmin, the primary fibrinolytic enzyme, is generated by the cleavage of the plasma protein, plasminogen, by its activator, tissue plasminogen activator. This reaction is regulated by plasminogen receptors at the surface of the vascular endothelial cells. Previous studies have identified the plasminogen receptor protein S100A10 as a key regulator of plasmin generation by cancer cells and macrophages. Here we examine the role of S100A10 and its annexin A2 binding partner in endothelial cell function using a homozygous S100A10-null mouse. Compared with wild-type mice, S100A10-null mice displayed increased deposition of fibrin in the vasculature and reduced clearance of batroxobin-induced vascular thrombi, suggesting a role for S100A10 in fibrinolysis in vivo. Compared with wild-type cells, endothelial cells from S100A10-null mice demonstrated a 40% reduction in plasminogen binding and plasmin generation in vitro. Furthermore, S100A10-deficient endothelial cells demonstrated impaired neovascularization of Matrigel plugs in vivo, suggesting a role for S100A10 in angiogenesis. These results establish an important role for S100A10 in the regulation of fibrinolysis and angiogenesis in vivo, suggesting S100A10 plays a critical role in endothelial cell function. (Blood. 2011;118(11): 3172-3181)

show abstract

Section: S100a10 and Fibrinolysis 3177supporting

confidence: 85%

Regulation of fibrinolysis by S100A10 in vivo

Surette

Madureira

Phipps

et al. 2011

Blood

111

View full text Add to dashboard Cite

show abstract

“…Aprotinin, a plasmin inhibitor in limited use in some countries, also suffers from a lack of specificity [1,5,6]. Several plasmin inhibitors being developed as antifibrinolytics include KDI-L17R [15] textilinin-1 [16] and cyclic peptidomimetics [13,14]. Yet, these are active site inhibitors and their selectivity for plasmin is challenging because of the similarity of active site geometries of a number of trypsin-like proteases.…”

Section: Discussionmentioning

confidence: 99%

“…These approaches include substrate-based design of linear and cyclic peptidomimetics [10][11][12][13][14], mutagenesis of key residues to engineer Kunitz-and Kazal-type protein/peptide inhibitors [15][16][17], covalent inhibition through a reactive nitrile or aldehyde warhead [18,19], and structure-based computational inhibitor design [20,21]. Each of these approaches typically targets the enzyme's active site.…”

Section: Rationale For Screening a Focused Library Of Sulfated Small mentioning

confidence: 99%

“…The monomeric scaffolds included chalcones (compounds 1-10), flavonoids (11)(12)(13)(14)(15)(16) [30][31][32], sucrose octasulfate (17) [40], quinazolinones (18 and 19) [37], and tetrahydro-isoquinolines (20)(21)(22)(23)(24)(25)(26)(27) [36], whereas the dimeric scaffolds comprised flavonoid-quinazolinone heterodimers (28)(29)(30)(31)(32)(33)(34) [37], bis-quinazolinones homodimers (35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47) [37], and bis-flavonoid homodimers (48-55). In addition to the inherent diversity of the scaffolds in this library, NSGMs also differed in the number (1 to 8) and orientation of the sulfate groups.…”

Section: Chemical Synthesis Of the Library Of Nsgmsmentioning

confidence: 99%

See 1 more Smart Citation

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

et al. 2015

View full text Add to dashboard Cite

Plasmin, a key serine protease, plays a major role in clot lysis and extracellular matrix remodeling. Heparin, a natural polydisperse sulfated glycosaminoglycan, is known to allosterically modulate plasmin activity. No small allosteric inhibitor of plasmin has been discovered to date. We screened an in-house library of 55 sulfated, small glycosaminoglycan mimetics based on nine distinct scaffolds and varying number and positions of sulfate groups to discover several promising hits. Of these, a pentasulfated flavonoid-quinazolinone dimer 32 was found to be the most potent sulfated small inhibitor of plasmin (IC50 = 45 μM, efficacy = 100%). Michaelis-Menten kinetic studies revealed an allosteric inhibition of plasmin by these inhibitors. Studies also indicated that the most potent inhibitors are selective for plasmin over thrombin and factor Xa, two serine proteases in coagulation cascade. Interestingly, different inhibitors exhibited different levels of efficacy (40%-100%), an observation alluding to the unique advantage offered by an allosteric process. Overall, our work presents the first small, synthetic allosteric plasmin inhibitors for further rational design.

show abstract

“…These protease inhibitors have been categorized into three classes, Kunitz, Kazal, and Bowman-Birk types (Conlon and Kim, 2000;Gebhard et al, 2004;Song et al, 2008). In addition to the well characterized serine protease inhibition functions of proteins such as trypsin and/or chymotrypsin Zhou et al, 2004;He et al, 2008;Choo et al, 2012;Wang et al, 2012), some serine protease inhibitors are known to be involved in various physiological processes such as ion channel blocking, blood coagulation, fibrinolysis, and inflammation (Masci et al, 2000;Flight et al, 2005Flight et al, , 2009Yuan et al, 2008;CorralRodríguez et al, 2009;Millers et al, 2009;Choo et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Molecular Cloning and Characterization of Chymotrypsin Inhibitor and Chitin-Binding Protein Homologs from the Bumblebee Bombus terrestris

Qiu¹,

Yoon²,

Jin³

2012

International Journal of Industrial Entomology

View full text Add to dashboard Cite

The bumblebee Bombus terrestris is widely used in greenhouses to pollinate crops. Here, we report the molecular cloning and characterization of chymotrypsin inhibitor and chitin-binding protein homologs from B. terrestris. Two cDNAs encoding chymotrypsin inhibitor (Bt-CI) and chitin-binding protein (Bt-CBP) homologs were cloned from B. terrestris. Gene sequence analysis showed that Bt-CI gene consists of three exons encoding 75 amino acids, including a predicted 20-amino acid signal peptide, while Bt-CBP consists of two exons encoding 78 amino acids, including a predicted 26-amino acid signal peptide. The mature Bt-CI and Bt-CBP peptides contain ten and six conserved cysteine residues, respectively. Database searches using the deduced sequences of Bt-CI and Bt-CBP showed similarity to those from B. impatiens (96% peptide sequence identities). Bt-CI and Bt-CBP were expressed in both the venom gland and fat body of B. terrestris worker bees. The recombinant Bt-CI and Bt-CBP peptides were expressed in baculovirusinfected insect cells. Taken together, our findings describe the molecular characterization of Bt-CI and Bt-CBP from B. terrestris.

show abstract

Textilinin‐1, an alternative anti‐bleeding agent to aprotinin: Importance of plasmin inhibition in controlling blood loss

Cited by 47 publications

References 21 publications

Regulation of fibrinolysis by S100A10 in vivo

Regulation of fibrinolysis by S100A10 in vivo

Plasmin Regulation through Allosteric, Sulfated, Small Molecules

Molecular Cloning and Characterization of Chymotrypsin Inhibitor and Chitin-Binding Protein Homologs from the Bumblebee Bombus terrestris

Contact Info

Product

Resources

About