kunitz inhibitor
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Author(s):  
B.P.O. Santos ◽  
E.S.F. Alves ◽  
C.S. Ferreira ◽  
A.F. D'Silva ◽  
A. Góes-Neto ◽  
...  


2020 ◽  
Vol 9 (11) ◽  
pp. 3684
Author(s):  
Kanagasabai Vadivel ◽  
Anne K. Zaiss ◽  
Yogesh Kumar ◽  
Frank M. Fabian ◽  
Ayman E. A. Ismail ◽  
...  

Current antifibrinolytic agents reduce blood loss by inhibiting plasmin active sites (e.g., aprotinin) or by preventing plasminogen/tissue plasminogen activator (tPA) binding to fibrin clots (e.g., ε-aminocaproic acid and tranexamic acid); however, they have adverse side effects. Here, we expressed 60-residue (NH2NAE…IEKCOOH) Kunitz domain1 (KD1) mutants of human tissue factor pathway inhibitor type-2 that inhibit plasmin as well as plasminogen activation. A single (KD1-L17R-KCOOH) and a double mutant (KD1-Y11T/L17R- KCOOH) were expressed in Escherichia coli as His-tagged constructs, each with enterokinase cleavage sites. KD1-Y11T/L17R-KCOOH was also expressed in Pichia pastoris. KD1-Y11T/L17R-KCOOH inhibited plasmin comparably to aprotinin and bound to the kringle domains of plasminogen/plasmin and tPA with Kd of ~50 nM and ~35 nM, respectively. Importantly, compared to aprotinin, KD1-L17R-KCOOH and KD1-Y11T/L17R-KCOOH did not inhibit kallikrein. Moreover, the antifibrinolytic potential of KD1-Y11T/L17R-KCOOH was better than that of KD1-L17R-KCOOH and similar to that of aprotinin in plasma clot-lysis assays. In thromboelastography experiments, KD1-Y11T/L17R-KCOOH was shown to inhibit fibrinolysis in a dose dependent manner and was comparable to aprotinin at a higher concentration. Further, KD1-Y11T/L17R-KCOOH did not induce cytotoxicity in primary human endothelial cells or fibroblasts. We conclude that KD1-Y11T/L17R-KCOOH is comparable to aprotinin, the most potent known inhibitor of plasmin and can be produced in large amounts using Pichia.



2018 ◽  
Vol 201 (2) ◽  
pp. 223-233 ◽  
Author(s):  
Heloisa Xavier Dib ◽  
Daniella Gorete Lourenço de Oliveira ◽  
Caio Fernando Ramalho de Oliveira ◽  
Gabriel Bonan Taveira ◽  
Erica de Oliveira Mello ◽  
...  


Biochimie ◽  
2018 ◽  
Vol 150 ◽  
pp. 37-47 ◽  
Author(s):  
Mey Ling Reytor González ◽  
Maday Alonso-del-Rivero Antigua ◽  
Lizbeth Hedstrom ◽  
Petr Kuzmič ◽  
José Ricardo Pires


2018 ◽  
Vol 66 (6) ◽  
pp. 1349-1358 ◽  
Author(s):  
Suellen Rodrigues Ramalho ◽  
Cézar da Silva Bezerra ◽  
Daniella Gorete Lourenço de Oliveira ◽  
Letícia Souza Lima ◽  
Simone Maria Neto ◽  
...  


2018 ◽  
Vol 118 (01) ◽  
pp. 090-102 ◽  
Author(s):  
Yunn-Hwa Ma ◽  
Chao-Wei Huang ◽  
Chih-Jen Wen ◽  
Yi-Ching Lu ◽  
Shiaw-Pyng Wey ◽  
...  

AbstractWithout conjunctive administration of an anticoagulant, endothelial injury-induced thrombosis is resistant to thrombolysis and prone to re-thrombosis. We hypothesized that co-delivery of recombinant tissue plasminogen activator (rtPA) with annexin V–containing anticoagulants that specifically target the injured endothelium may passivate the thrombogenic elements of the vascular injury site and enhance rtPA-induced thrombolysis. In this study, the effects of conjunctive administration of Kinexins (Kunitz inhibitor–annexin V fusion proteins) with rtPA on thrombolysis were determined in vitro and in vivo. Thromboelastometry showed that both TAP-A (tick anticoagulant peptide–annexin V fusion protein; an inhibitor of factor Xa [FXa] and prothrombinase) and A-6L15 (annexin V-6L15 fusion protein; an inhibitor of tissue factor/FVIIa) exerted concentration-dependent (10–100 nM) effects on clot formation, with TAP-A being several folds more potent than A-6L15 in whole blood. Combination of TAP-A or A-6L15 with rtPA (1 μg/mL) led to decrease in lysis index, suggesting conjunctive enhancement of thrombolysis by combined use of rtPA with TAP-A or A-6L15. In a rat cremaster muscle preparation subjected to photochemical injury, conjunctive administration of rtPA and TAP-A significantly restored tissue perfusion to 56%, which is approximately two fold of that by rtPA or TAP-A alone. Near-infrared fluorescence images demonstrated local retention of a fluorescent A-6L15-S288 at the injury site, suggesting a targeting effect of the fusion protein. Pharmacokinetic analysis showed that 123I-labelled TAP-A and A-6L15 had initial distribution half-lives (T1/2α) of approximately 6 minutes and elimination half-lives (T1/2β) of approximately 2.3 hours. In conclusion, Kinexins were potentially useful adjunctive agents with rtPA thrombolytic therapy especially for thrombosis induced by endothelial injury.



2017 ◽  
Vol 73 (a2) ◽  
pp. C271-C271
Author(s):  
Ameya Dipak Bendre ◽  
Sureshkumar Ramasamy ◽  
C. G. Suresh




2016 ◽  
Vol 51 (6) ◽  
pp. 792-803 ◽  
Author(s):  
Cézar da Silva Bezerra ◽  
Caio Fernando Ramalho de Oliveira ◽  
Olga Lima Tavares Machado ◽  
Gabriela Souto Vieira de Mello ◽  
Maira Galdino da Rocha Pitta ◽  
...  


2016 ◽  
Vol 61 (3) ◽  
pp. 271-279 ◽  
Author(s):  
Sladjana Stanojevic ◽  
Miroljub Barac ◽  
Mirjana Pesic ◽  
Biljana Vucelic-Radovic

Kunitz inhibitor (KTI) and Bowman-Birk trypsin inhibitor (BBI) are inhibitors of digestive enzymes in raw soybeans. Due to their antinutritive properties in the active state, their inactivation by heat treatment is commonly used. Soymilk is a turbid and stable colloidal solution, obtained by thermal treatment of soybean. In this study soymilk was made on a pilot-plant scale from six soybean cultivars using hydrothermal cooking (HTC) as the production method. This procedure is significantly different from the traditional one. The aim of this investigation was to evaluate the impact of the HTC processing for soymilk production and different soybean genotypes on trypsin inhibitor content and activity. Obtained soymilk contained BBI in trace amounts, in the BBI-polymeric forms. The BBI monomeric forms were not detected. The soymilk of the investigated soybean genotypes had very similar KTI levels (2.34-2.99%). Results have suggested that the soybean genotype does not have substantial effects on the levels of KTI, as well as on the value of residual trypsin inhibitor activity (rTIA). The total content of TI and rTIA showed a strong dependence (r=0.91; p<0.05). HTC-soymilk rTIA was <20% (7.15-19.89%). These results have indicated that HTC processed soymilk is applicable for human consumption.



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