Isfahan University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Design and Production of New Chimeric Reteplase With Enhanced Fibrin Affinity: A Theoretical and Experimental Study Publisher Pubmed



Mohammadi E1 ; Mahnam K2 ; Jahaniannajafabadi A1 ; Sadeghi HMM1
Authors
Show Affiliations
Authors Affiliations
  1. 1. Department of Pharmaceutical Biotechnology, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
  2. 2. Faculty of Science, Department of Biology, Shahrekord University, Shahrekord, Iran

Source: Journal of Biomolecular Structure and Dynamics Published:2021


Abstract

Plasminogen activators (PAs) are widely used for treatment of disorders caused by clot formation. Fibrin specific PAs are safe drugs from this group because of reducing the incidence of hemorrhage. The newer generation of PAs like tenecteplase, reteplase and desmoteplase were designed with the aim of achieving desirable properties such as improving specificity and affinity to fibrin and increasing half-life. Protein engineering and using of theoretical methods can help to rational and reliable design of new PAs with a set of favorable properties. In the present study, two new chimeric reteplase named M1-chr and M2-chr were designed with the aim of enhancing fibrin affinity also some potential properties include of increasing resistance to plasminogen activator inhibitor-1 and decreasing neurotoxicity. So, finger domain of desmoteplase was added to reteplase as a high fibrin specific domain. Some other point mutations were considering to achieve other mentioned properties. Three dimensional structure of wild-type reteplase and mutants were created by homology modeling and were evaluated by molecular dynamic simulation. Then, mutants docked to fibrin by HADDOCK web tools. Result of theoretical section verified the stability of mutants’ structures. Also showed better interaction between M1-chr with fibrin than M2-chr. Wild-type and mutants were produced in bacterial expression system. Experimental assessment showed both mutants have appropriate enzymatic activity also 1.9-fold fibrin binding ability compared to wild-type. Therefore, this study offers new thrombolytic drugs with desirable properties specially enhanced fibrin affinity so they can represent a promising future in cost-effective production of favorable thrombolytic drugs. Communicated by Ramaswamy H. Sarma. © 2020 Informa UK Limited, trading as Taylor & Francis Group.
Related Docs
View other Related Docs
1. Rational Design of a New Variant of Reteplase With Optimized Physicochemical Profile and Large-Scale Production in Escherichia Coli, World Journal of Microbiology and Biotechnology (2022)
2. Improving the Solubility, Activity, and Stability of Reteplase Using in Silico Design of New Variants, Research in Pharmaceutical Sciences (2019)
3. Reteplase: Structure, Function, and Production, Advanced Biomedical Research (2019)
4. The Effect of Mutation on Neurotoxicity Reduction of New Chimeric Reteplase, a Computational Study, Research in Pharmaceutical Sciences (2023)
5. Investigation of Supercharging As a Strategy to Enhance the Solubility and Plasminogen Cleavage Activity of Reteplase, Iranian Journal of Biotechnology (2020)
6. Bacterial Staphylokinase As a Promising Third-Generation Drug in the Treatment for Vascular Occlusion, Molecular Biology Reports (2020)
7. Computational Design of a Potential Therapeutic Peptide Against Spike Protein of Sars-Cov-2, Journal of Computational Biophysics and Chemistry (2021)
8. Comparison of the Cytoplasmic and Periplasmic Production of Reteplase in Escherichia Coli, Preparative Biochemistry and Biotechnology (2013)
Experts (# of related papers)
View all Related Experts
Hamid Mirmohammad Sadeghi (11)
Vajihe Akbari (5)
Other Related Docs
9. Improvement of Soluble Production of Reteplase in Escherichia Coli by Optimization of Chemical Chaperones in Lysis Buffer, Advanced Biomedical Research (2019)
10. Optimization of the Expression of Reteplase in Escherichia Coli Top10 Using Arabinose Promoter, Jundishapur Journal of Natural Pharmaceutical Products (2015)
11. Identification and Characterization of a Novel Nanobody Against Human Placental Growth Factor to Modulate Angiogenesis, Molecular Immunology (2016)
12. Construction of Tenecteplase Coding Sequence by a Rapid Megaprimer Pcr Method and Its Cloning in a Mammary Gland Tissue Specific Expression Vector, Research in Pharmaceutical Sciences (2009)
13. Optimization of Buffer Additives for Efficient Recovery of Hgm-Csf From Inclusion Bodies Using Response Surface Methodology, Iranian Journal of Pharmaceutical Research (2020)
14. Rational Design of a New Mutant of Tobacco Etch Virus Protease in Order to Increase the in Vitro Solubility, Research in Pharmaceutical Sciences (2020)
15. Cloning and Expression of Functional Reteplase in Escherichia Coli Top10, Avicenna Journal of Medical Biotechnology (2013)
16. Design of a Novel Metal Binding Peptide by Molecular Dynamics Simulation to Sequester Cu and Zn Ions, Research in Pharmaceutical Sciences (2014)
17. Optimization of Fermentation Conditions for Reteplase Expression by Escherichia Coli Using Response Surface Methodology, Avicenna Journal of Medical Biotechnology (2019)
18. Computational Design of Newly Engineered Darpins As Her2 Receptor Inhibitors for Breast Cancer Treatment, Research in Pharmaceutical Sciences (2023)
19. Creation of Tenecteplase-Producing Cho Cell Line Using Site-Specific Integrase From the Phage Φc31, Yakhteh (2010)
20. Improvement of Solubility and Yield of Recombinant Protein Expression in E. Coli Using a Two-Step System, Research in Pharmaceutical Sciences (2019)
21. In Silico Analysis of Transmembrane Protein 31 (Tmem31)Antigen to Design Novel Multiepitope Peptide and Dna Cancer Vaccines Against Melanoma, Molecular Immunology (2019)
22. Expression of the Recombinant Plasminogen Activator (Reteplase) by a Non-Lytic Insect Cell Expression System, Research in Pharmaceutical Sciences (2013)