Design of a novel chimeric tissue plasminogen activator with favorable Vampire bat plasminogen activator properties

Kazemali, MohammadReza; Majidzadeh‐A, Keivan; Sardari, Soroush; Saadatirad, Amir Hossein; Khalaj, Vahid; Zarei, Najmeh; Barkhordari, Farzaneh; Abdolzadeh, Ahmad; Mahboudi, Fereidoun

doi:10.1016/j.enzmictec.2014.09.005

Cited by 5 publications

(9 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…60 Substitution of the alteplase F-domain with the corresponding domain of desmoteplase and the removal of the K2 domain increased the affinity to fibrin by 1.2-fold and provided fibrin stimulatory effect of up to 1,560 times. 61 A similar F-domain replacement and deletion of the lysine binding site of the K2 domain resulted in a 1.2-fold greater affinity to fibrin and a 14-fold higher fibrin stimulatory effect. 61,62 Clinical trials, such as Desmoteplase in Acute Ischemic Stroke (DIAS) 63 and Dose Escalation of Desmoteplase in Acute Ischemic Stroke (DEDAS), have revealed that desmoteplase has high recanalization (up to 53.3% in patients treated with 125 µg/kg desmoteplase) and low intracranial hemorrhage (0%) rates.…”

Section: Desmoteplasementioning

confidence: 95%

“…61 A similar F-domain replacement and deletion of the lysine binding site of the K2 domain resulted in a 1.2-fold greater affinity to fibrin and a 14-fold higher fibrin stimulatory effect. 61,62 Clinical trials, such as Desmoteplase in Acute Ischemic Stroke (DIAS) 63 and Dose Escalation of Desmoteplase in Acute Ischemic Stroke (DEDAS), have revealed that desmoteplase has high recanalization (up to 53.3% in patients treated with 125 µg/kg desmoteplase) and low intracranial hemorrhage (0%) rates. 64 DIAS-2 and DIAS-3 trials have confirmed that it is a safe thrombolytic drug.…”

Section: Desmoteplasementioning

confidence: 95%

See 1 more Smart Citation

Development and Testing of Thrombolytics in Stroke

Nikitin¹,

Choi

Mičan³

et al. 2021

J Stroke

View full text Add to dashboard Cite

Despite recent advances in recanalization therapy, mechanical thrombectomy will never be a treatment for every ischemic stroke because access to mechanical thrombectomy is still limited in many countries. Moreover, many ischemic strokes are caused by occlusion of cerebral arteries that cannot be reached by intra-arterial catheters. Reperfusion using thrombolytic agents will therefore remain an important therapy for hyperacute ischemic stroke. However, thrombolytic drugs have shown limited efficacy and notable hemorrhagic complication rates, leaving room for improvement. A comprehensive understanding of basic and clinical research pipelines as well as the current status of thrombolytic therapy will help facilitate the development of new thrombolytics. Compared with alteplase, an ideal thrombolytic agent is expected to provide faster reperfusion in more patients; prevent re-occlusions; have higher fibrin specificity for selective activation of clot-bound plasminogen to decrease bleeding complications; be retained in the blood for a longer time to minimize dosage and allow administration as a single bolus; be more resistant to inhibitors; and be less antigenic for repetitive usage. Here, we review the currently available thrombolytics, strategies for the development of new clot-dissolving substances, and the assessment of thrombolytic efficacies <i>in vitro</i> and <i>in vivo</i>.

show abstract

Section: Desmoteplasementioning

confidence: 95%

Section: Desmoteplasementioning

confidence: 95%

Development and Testing of Thrombolytics in Stroke

Nikitin¹,

Choi

Mičan³

et al. 2021

J Stroke

View full text Add to dashboard Cite

show abstract

“…The variant also has the lysine binding site in K2 defunct via the Trp254Arg mutation [114]. Higher fibrin binding and fibrin stimulation were achieved by substituting the finger domain of t-PA by that of desmoteplase and deleting the K2 domain [132].…”

Section: Tissue Plasminogen Activatormentioning

confidence: 99%

“…Since desmoteplase exhibits plenty of positive properties and not many drawbacks, a little effort was put into its engineering. A chimeric protein combining the structures of desmoteplase and tenecteplase has been recently reported [132,323]. In this variant, the kringle 2 domain of tenecteplase was deleted and the finger domain was exchanged for the domain of desmoteplase with the aim to improve the protein’s fibrin specificity.…”

Section: Desmoteplasementioning

confidence: 99%

“…In this variant, the kringle 2 domain of tenecteplase was deleted and the finger domain was exchanged for the domain of desmoteplase with the aim to improve the protein’s fibrin specificity. However, the constructed variant was only 8-fold more specific than t-PA but 25-fold less specific compared to desmoteplase [132]. Another approach was focused on preventing the creation of the two-chain form of t-PA.…”

Section: Desmoteplasementioning

confidence: 99%

See 1 more Smart Citation

Structural Biology and Protein Engineering of Thrombolytics

Mičan

Toul

Bednář

et al. 2019

Computational and Structural Biotechnology Journal

View full text Add to dashboard Cite

Myocardial infarction and ischemic stroke are the most frequent causes of death or disability worldwide. Due to their ability to dissolve blood clots, the thrombolytics are frequently used for their treatment. Improving the effectiveness of thrombolytics for clinical uses is of great interest. The knowledge of the multiple roles of the endogenous thrombolytics and the fibrinolytic system grows continuously. The effects of thrombolytics on the alteration of the nervous system and the regulation of the cell migration offer promising novel uses for treating neurodegenerative disorders or targeting cancer metastasis. However, secondary activities of thrombolytics may lead to life-threatening side-effects such as intracranial bleeding and neurotoxicity. Here we provide a structural biology perspective on various thrombolytic enzymes and their key properties: (i) effectiveness of clot lysis, (ii) affinity and specificity towards fibrin, (iii) biological half-life, (iv) mechanisms of activation/inhibition, and (v) risks of side effects. This information needs to be carefully considered while establishing protein engineering strategies aiming at the development of novel thrombolytics. Current trends and perspectives are discussed, including the screening for novel enzymes and small molecules, the enhancement of fibrin specificity by protein engineering, the suppression of interactions with native receptors, liposomal encapsulation and targeted release, the application of adjuvants, and the development of improved production systems.

show abstract

Research progress on the fibrinolytic enzymes produced from traditional fermented foods

Wang

Peng

Xie

et al. 2023

Food Science & Nutrition

View full text Add to dashboard Cite

Cardiovascular diseases (CVDs) are a global health problem and leading cause of death worldwide. Thrombus formation, one of the CVDs, is essentially the formation of fibrin clots. The existing thrombolytic agents have the disadvantages of high price, short half‐life, and high bleeding risk; hence, there is an urgent need to find the alternative thrombolytic agents. In recent years, traditional fermented foods have been widely investigated for their outstanding effects in the prevention and treatment of thrombus formation. In this review, we have focused on fibrinolytic enzymes produced by microorganisms during the fermentation of traditional fermented foods and their potential use for treating CVDs. First, we discussed about the sources of fibrinolytic enzymes and microbial strains that produce those enzymes followed by the optimization of fermentation process, purification, and physicochemical properties of fibrinolytic enzymes. Finally, we have summarized the thrombolytic effects of fibrinolytic enzymes in humans and mice. Fibrinolytic enzymes produced by microorganisms during the fermentation of traditional fermented foods not only lyse thrombi but also acts as anti‐atherosclerotic, anti‐hyperlipidemia, and neuroprotection agents. Therefore, fibrinolytic enzymes from traditional fermented foods have great potential for the prevention and treatment of CVDs.

show abstract

Design of a novel chimeric tissue plasminogen activator with favorable Vampire bat plasminogen activator properties

Cited by 5 publications

References 37 publications

Development and Testing of Thrombolytics in Stroke

Development and Testing of Thrombolytics in Stroke

Structural Biology and Protein Engineering of Thrombolytics

Research progress on the fibrinolytic enzymes produced from traditional fermented foods

Contact Info

Product

Resources

About