Preparation, characterization and molecular modeling of PEGylated human growth hormone with agonist activity

Khameneh, Bahman; Jaafari, Mahmoud Reza; Hassanzadeh-Khayyat, Mohammad; Varasteh, Abdolreza; Chamani, Jamshidkhan; Iranshahi, Mehrdad; Mohammadpanah, Hamid; Abnous, Khalil; Saberi, Mohammad Reza

doi:10.1016/j.ijbiomac.2015.06.037

Cited by 19 publications

(9 citation statements)

References 37 publications

(52 reference statements)

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“…Mu et al showed that PEG size and PEG-conjugated position modulate the hydrodynamic volume of the Staphylokinase-PEG complex and the flexibility of grafted PEG chains [53]. Khameneh et al simulated PEGylated human growth hormone with its receptor and performed the docking analysis, showing the random-coil formation of PEG and the reduced binding affinity between human growth hormone and its receptor in the presence of PEG [54]. The Accardo group simulated PEGylated hexa-phenylalanine [55,56], tetra-tryptophan [57], and tyrosine-containing aromatic peptides [58], showing the effect of PEGylation on the conformation and stability of assembled structures.…”

Section: Proteinsmentioning

confidence: 99%

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

Lee

2020

Pharmaceutics

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Since the first polyethylene glycol (PEG)ylated protein was approved by the FDA in 1990, PEGylation has been successfully applied to develop drug delivery systems through experiments, but these experimental results are not always easy to interpret at the atomic level because of the limited resolution of experimental techniques. To determine the optimal size, structure, and density of PEG for drug delivery, the structure and dynamics of PEGylated drug carriers need to be understood close to the atomic scale, as can be done using molecular dynamics simulations, assuming that these simulations can be validated by successful comparisons to experiments. Starting with the development of all-atom and coarse-grained PEG models in 1990s, PEGylated drug carriers have been widely simulated. In particular, recent advances in computer performance and simulation methodologies have allowed for molecular simulations of large complexes of PEGylated drug carriers interacting with other molecules such as anticancer drugs, plasma proteins, membranes, and receptors, which makes it possible to interpret experimental observations at a nearly atomistic resolution, as well as help in the rational design of drug delivery systems for applications in nanomedicine. Here, simulation studies on the following PEGylated drug topics will be reviewed: proteins and peptides, liposomes, and nanoparticles such as dendrimers and carbon nanotubes.

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Section: Proteinsmentioning

confidence: 99%

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

Lee

2020

Pharmaceutics

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“…50 In another study, Ghasemi et al confirmed the stability of the hGH in MPEG-PLA and PLA-PEG-PLA nanoparticles. 23 Khameneh et al 59 reported the helical content of the native protein and the PEGylated protein as 51.05 ± 0.3 and 50.77 ± 0.3%, respectively, indicating that the secondary structure content remained mostly intact. In another study, the two PEGylation approaches of hGH were compared, and the structural analysis showed that neither had a destructive effect on the protein conformation and stability.…”

Section: Resultsmentioning

confidence: 99%

Insight into the Microcosm of the Human Growth Hormone and Its Interactions with Polymers and Copolymers: A Molecular Dynamics Perspective

et al. 2020

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Therapeutic proteins nowadays have increasingly been applied for their considerable potential in treating a wide variety of diseases. The effectiveness and potency of native therapeutic proteins are limited by various factors (e.g., stability, blood circulation time, specificity). Over the past years, a great deal of effort has been devoted to developing safe and efficient protein delivery systems. Entrapment of protein into polymeric and copolymeric matrices is common among the different types of proteinbased drug formulation. However, despite the massive efforts toward developing therapeutic protein delivery in experimental studies and industrial applications, there is relatively little data on the influence of polymers and copolymers on therapeutic proteins at the atomic and molecular levels. Herein, molecular dynamics (MD) simulations are used to study the effects of biocompatible synthetic polymers including methoxy poly(ethylene glycol) (MPEG), poly(lactic acid) (PLA), and poly(lactic acid) copolymers (poly(lacticco-glycolic acid)) PLGA and MPEG-PLA(PELA)) on the structure and dynamics of the human growth hormone (hGH), and the results are compared with previous experimental findings. Our results indicate that the hGH conformation remains stable both in pure water and in the presence of polymers, and these results are in good agreement with previous experimental data. It is shown that the MPEG chains are self-assembled and folded into a semicrystalline structure; therefore, only a small portion of the protein interacts with the polymer. The other three polymers, however, interact well with the protein and partially cover its surface. Our findings suggest that the use of these polymers for protein encapsulation has the advantage of reducing protein aggregation and thus increasing drug serum half-life. Eventually, we anticipate that the research results will expand the current knowledge about encapsulation mechanisms and the molecular interactions between hGH and the polymers.

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“…PEGs conjugation of therapeutic proteins, defined as PEGylation, has been used to decrease proteins’ immunogenicity, which is relevant for the improvement of the pharmacological proprieties of drugs [ 203 , 204 ]. By exploiting TGs’ requirements for sequence and structure specificity for the targeting of Gln residues (amine acceptor site) [ 205 ], different groups have shown that classical random conjugation of PEG on proteins, which produces heterogeneous results, can be replaced by the more efficient TGs-dependent PEGylation (by mTG and FXIIIa), which allows the production of single site-specific conjugate isomers and, at the same time, the preservation of the proteins’ bioactivities [ 206 , 207 , 208 , 209 , 210 ]. Interestingly, Sato et al showed that the mTG-mediated incorporation of site-specific alkylamine-PEG conjugates into recombinant human interleukin-2 (rhIL-2), acting as the Gln donor substrate, did not affect rhIL-2 bioactivity, as opposed to random derivatisation.…”

Section: Tgs Crosslinking Activity In Biotechnological Applicationmentioning

confidence: 99%

Biocatalysis by Transglutaminases: A Review of Biotechnological Applications

et al. 2018

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The biocatalytic activity of transglutaminases (TGs) leads to the synthesis of new covalent isopeptide bonds (crosslinks) between peptide-bound glutamine and lysine residues, but also the transamidation of primary amines to glutamine residues, which ultimately can result into protein polymerisation. Operating with a cysteine/histidine/aspartic acid (Cys/His/Asp) catalytic triad, TGs induce the post-translational modification of proteins at both physiological and pathological conditions (e.g., accumulation of matrices in tissue fibrosis). Because of the disparate biotechnological applications, this large family of protein-remodelling enzymes have stimulated an escalation of interest. In the past 50 years, both mammalian and microbial TGs polymerising activity has been exploited in the food industry for the improvement of aliments’ quality, texture, and nutritive value, other than to enhance the food appearance and increased marketability. At the same time, the ability of TGs to crosslink extracellular matrix proteins, like collagen, as well as synthetic biopolymers, has led to multiple applications in biomedicine, such as the production of biocompatible scaffolds and hydrogels for tissue engineering and drug delivery, or DNA-protein bio-conjugation and antibody functionalisation. Here, we summarise the most recent advances in the field, focusing on the utilisation of TGs-mediated protein multimerisation in biotechnological and bioengineering applications.

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Preparation, characterization and molecular modeling of PEGylated human growth hormone with agonist activity

Cited by 19 publications

References 37 publications

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

Molecular Simulations of PEGylated Biomolecules, Liposomes, and Nanoparticles for Drug Delivery Applications

Insight into the Microcosm of the Human Growth Hormone and Its Interactions with Polymers and Copolymers: A Molecular Dynamics Perspective

Biocatalysis by Transglutaminases: A Review of Biotechnological Applications

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