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Fibrinolytic Enzymes for Thrombolytic Therapy
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Swaroop S. Kumar, Sabu Abdulhameed
Staphylokinase is another non-t-PA variant belonging to the third-generation plasminogen activators. It is an extracellular protein produced by Staphylococcus aureus, which forms 1:1 stoichiometric complex with plasmin or plasminogen and activates more plasminogen molecules. SAK is a monomer of 136 amino acids without any disulfide bond and molecular weight is about 15.5 KDa. SAK complexes with plasminogen molecules that are bound to partially degraded fibrin [Sakharov et al., 1996]. α2-antiplasmin inhibits plasminogen-SAK complex in the absence of fibrin, however, in presence of fibrin the lysine binding domain of the complex is occupied, preventing the inhibition by α2-antiplasmin and there is a 4-fold increment in activity with presence of fibrin, thus more specificity towards fibrin (Lijnen et al., 1991).
Plasma Protein Function in Hemostasis
Published in Genesio Murano, Rodger L. Bick, Basic Concepts of Hemostasis and Thrombosis, 2019
Of the several activators of plasminogen, the best known are (1) urokinase, a proteolytic enzyme synthesized by the kidney and found in normal urine; (2) activators from various tissues, (3) streptokinase (produced by β-hemolytic streptococci), and (4) sta-phylokinase (from staphylococci). Purified urokinase directly converts plasminogen to plasmin by proteolysis.109, 118 Streptokinase, a nonproteolytic enzyme, first forms a complex with the substrate (plasminogen) or the enzyme (plasmin) itself.109, 118 This results in an “activator” that converts plasminogen to plasmin. Staphylokinase converts plasminogen to plasmin by a mechanism similar to that of streptokinase.119 Other activators are produced locally, some arising from the vascular endothelium120,121 in response to a variety of stimuli such as injury, ischemia, exercise, pyrogens, epinephrine, electroshock, etc.118 It is not clear whether endothelial cell activator activates plasminogen directly or through a proactivator. Activated Protein-C may be involved in this system.
Staphylococcus aureus
Published in Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward, Case Studies in Infectious Disease, 2010
Peter M. Lydyard, Michael F. Cole, John Holton, William L. Irving, Nino Porakishvili, Pradhib Venkatesan, Katherine N. Ward
Almost all strains of S. aureus secrete a group of enzymes and cytotoxins that includes four hemolysins (alpha, beta, gamma, and delta), nucleases, proteases, lipases, hyaluronidase, and collagenase. Alpha-toxin is a pore-forming toxin that acts on many types of human cells. It is dermonecrotic and neurotoxic. Beta-toxin is a sphingomyelinase C whose role in pathogenesis remains unclear. Delta-toxin is able to damage the membrane of many human cells, possibly by inserting into the cytoplasmic membrane and disordering lipid chain dynamics, although there are suggestions that it may form pores. Two types of bicomponent toxin are made by S. aureus, gamma-toxin and Panton-Valentine leukocidin (PVL). While gamma-toxin is produced by almost all strains of S. aureus, PVL is produced by only a few percent of strains. The toxins affect neutrophils and macrophages. PVL has pore-forming activity and has been associated with necrotic lesions involving the skin and with severe necrotizing pneumonia in community-acquired S. aureus infections. Also, S. aureus produces a staphylokinase, which is a potent activator of plasminogen, the precursor of the fibrinolytic protease plasmin.
Investigational drugs for ischemic stroke: what’s in the clinical development pipeline for acute phase and prevention?
Published in Expert Opinion on Investigational Drugs, 2022
Maria Giulia Mosconi, Maurizio Paciaroni, Walter Ageno
Recombinant staphylokinase is another investigational thrombolytic agent that is a modified recombinant staphylokinase having low immunogenicity, high thrombolytic activity, and selectivity to fibrin. The Russian FRIDA study (NCT03151993) was a phase 3 study on the efficacy and safety of single bolus injection of recombinant non-immunogenic Staphylokinase (Fortelyzin) compared to a bolus infusion of alteplase for patients with AIS. A total of 336 patients (87%) were included in the trial. Non-immunogenic staphylokinase was reported to be non-inferior to alteplase for patients with acute ischemic stroke. Mortality, symptomatic intracranial hemorrhage, and serious adverse events did not differ significantly between groups. Endpoints were analyzed in the per-protocol population, which was identical to the intention-to-treat population. These are promising results but future studies are needed to continue to assess the safety and efficacy of non-immunogenic staphylokinase in patients with acute ischemic stroke [83].
Relationship between nasopharyngeal microbiota and patient’s susceptibility to viral infection
Published in Expert Review of Anti-infective Therapy, 2019
Grégory Dubourg, Sophie Edouard, Didier Raoult
At present, very little is known about how respiratory commensals could promote the incidence or severity of viral respiratory infections. Indeed, there is apparently no competition between viruses and bacteria for colonizing the nasopharyngeal microbiota, as could be observed in the case of Clostridium difficile infections, despite the fact that mice treated with antibiotics were more susceptible to viral infections. To date, the most probable hypothesis relies on immunological properties of microbes inhabiting the nasopharynx and, by extension, the respiratory tract. By priming with Toll Like Receptor (TLR) 2, S. aureus was actually able to reduce the severity of lung damage in a model of H1N1 influenza infection in mice by M2 alveolar macrophages, thereby reducing the inflammation of the lungs due to influenza. The protective influence of S. aureus but also of S. epidermidis on the respiratory tract has also been shown to be effective against infections caused by K. pneumoniae and S. pneumoniae by stimulating Nod-like receptor [69]. However, this mechanism could be strain-dependent, as it was shown that several enzymes (i.e., staphylokinase or protease) produced by some S. aureus isolates could enhance viral replication, and thereby promote influenza pneumonia [70,71].
Recent advances in targeted delivery of tissue plasminogen activator for enhanced thrombolysis in ischaemic stroke
Published in Journal of Drug Targeting, 2018
Masumeh Zamanlu, Mehdi Farhoudi, Morteza Eskandani, Javad Mahmoudi, Jaleh Barar, Mohammad Rafi, Yadollah Omidi
Among a number of agents introduced in various generations, some of them have been approved for the clinical thrombolytic therapy, including: the first generation for indications other than stroke, the agents of second generation except scuPA for different indications including stroke, and the third generation tenecteplase together with reteplase. Yet, there are some other newly developed thrombolytic agents (e.g. a mutant tPA Monteplase and staphylokinase) underway towards translation into clinical applications [64,65]. Summary of studies on some of the modified plasminogen activators is presented in Table 2.