PEGylation of Truncated Streptokinase Leads to Formulation of a Useful Drug with Ameliorated Attributes

Sawhney, Pooja; Katare, Keya; Sahni, Girish

doi:10.1371/journal.pone.0155831

Cited by 14 publications

(14 citation statements)

References 51 publications

(66 reference statements)

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“…Preventing the cleavage by mutagenesis at the identified positions (Lys59Gln/Glu, Lys386Gln) resulted in a 21-fold increased half-life without affecting activity [[235], [236], [237]]. Alternative strategies based on combinatorial mutagenesis [14,238], PEGylation [[239], [240], [241], [242]], glycosylation [235,243], or lipidification [244] yielded streptokinase variants with improved thrombolytic activity, decreased immunogenicity, and higher half-life.…”

Section: Streptokinasementioning

confidence: 99%

Structural Biology and Protein Engineering of Thrombolytics

Mičan

Toul

Bednář

et al. 2019

Computational and Structural Biotechnology Journal

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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.

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Section: Streptokinasementioning

confidence: 99%

Structural Biology and Protein Engineering of Thrombolytics

Mičan

Toul

Bednář

et al. 2019

Computational and Structural Biotechnology Journal

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“…63 PEGylated systems of truncated SK variants with promising in vitro fibrinolytic activity and enhanced in vivo circulation residence time have also been reported recently, although the in vivo fibrinolytic capacity of these systems were not reported. 67 In preclinical ex vivo studies using beagles, PEG-conjugated urokinase was able to maintain fibrinolytic capacity for long periods of time (i.e., prolonged bioactivity in plasma), while free urokinase rapidly lost its activity in plasma due to inhibitor effects. 64 Recombinant tPA has also been conjugated to PEG and the PEG-tPA product was reported to show partial enhancement of circulation lifetime and bioactivity compared with free tPA in canine models.…”

Section: Direct Modification Of Therapeutic Agentsmentioning

confidence: 99%

Vascular Nanomedicine: Current Status, Opportunities, and Challenges

Sun

Gupta

2019

Semin Thromb Hemost

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The term “nanotechnology” was coined by Norio Taniguchi in the 1970s to describe the manipulation of materials at the nano (10−9) scale, and the term “nanomedicine” was put forward by Eric Drexler and Robert Freitas Jr. in the 1990s to signify the application of nanotechnology in medicine. Nanomedicine encompasses a variety of systems including nanoparticles, nanofibers, surface nano-patterning, nanoporous matrices, and nanoscale coatings. Of these, nanoparticle-based applications in drug formulations and delivery have emerged as the most utilized nanomedicine system. This review aims to present a comprehensive assessment of nanomedicine approaches in vascular diseases, emphasizing particle designs, therapeutic effects, and current state-of-the-art. The expected advantages of utilizing nanoparticles for drug delivery stem from the particle's ability to (1) protect the drug from plasma-induced deactivation; (2) optimize drug pharmacokinetics and biodistribution; (3) enhance drug delivery to the disease site via passive and active mechanisms; (4) modulate drug release mechanisms via diffusion, degradation, and other unique stimuli-triggered processes; and (5) biodegrade or get eliminated safely from the body. Several nanoparticle systems encapsulating a variety of payloads have shown these advantages in vascular drug delivery applications in preclinical evaluation. At the same time, new challenges have emerged regarding discrepancy between expected and actual fate of nanoparticles in vivo, manufacturing barriers of complex nanoparticle designs, and issues of toxicity and immune response, which have limited successful clinical translation of vascular nanomedicine systems. In this context, this review will discuss challenges and opportunities to advance the field of vascular nanomedicine.

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“…35 PEGylation of streptokinase has been attempted as a strategy to extend its half-life and reduce immunogenicity. 1,36 However, such modifications compromised its plasminogen activation ability. 1 Recently, PEGylated mutants of streptokinase have been created with clot specificity.…”

Section: First Generation Plasminogen Activatorsmentioning

confidence: 99%

“…1 Recently, PEGylated mutants of streptokinase have been created with clot specificity. 36 Streptokinase derivatives with platelet glycoprotein binding domains have been developed that produced a higher localized concentration of plasmin in vivo. 1 Recombinant SK with minimized immunoreactivity has been produced.…”

Section: First Generation Plasminogen Activatorsmentioning

confidence: 99%

The evolution of recombinant thrombolytics: Current status and future directions

Adivitiya

Khasa

2016

Bioengineered

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Cardiovascular disorders are on the rise worldwide due to alcohol abuse, obesity, hypertension, raised blood lipids, diabetes and age-related risks. The use of classical antiplatelet and anticoagulant therapies combined with surgical intervention helped to clear blood clots during the inceptive years. However, the discovery of streptokinase and urokinase ushered the way of using these enzymes as thrombolytic agents to degrade the fibrin network with an issue of systemic hemorrhage. The development of second generation plasminogen activators like anistreplase and tissue plasminogen activator partially controlled this problem. The third generation molecules, majorly t-PA variants, showed desirable properties of improved stability, safety and efficacy with enhanced fibrin specificity. Plasmin variants are produced as direct fibrinolytic agents as a futuristic approach with targeted delivery of these drugs using liposome technlogy. The novel molecules from microbial, plant and animal origin present the future of direct thrombolytics due to their safety and ease of administration.

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PEGylation of Truncated Streptokinase Leads to Formulation of a Useful Drug with Ameliorated Attributes

Cited by 14 publications

References 51 publications

Structural Biology and Protein Engineering of Thrombolytics

Structural Biology and Protein Engineering of Thrombolytics

Vascular Nanomedicine: Current Status, Opportunities, and Challenges

The evolution of recombinant thrombolytics: Current status and future directions

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