Current Issue : July - September Volume : 2019 Issue Number : 3 Articles : 5 Articles
The major obstacle facing efficient gene therapy is the development of reliable delivery\nvehicles, which are both nontoxic and biocompatible and possess efficient cell-specific gene delivery.\nPreviously, hybrid delivery vehicles comprising anionic liposomes and cationic polymers have\nbeen used successfully for gene therapy. In this study, hybrid vectors based on glycosylated\nartificial viral envelopes (including two novel compositions mimicking HIV and HSV envelopes)\nand polyethylenimine were morphologically and physiologically characterised. Transfection studies\nshowed that the hybrid vectors based on the control liposomes, and their glycosylated modifications,\nhad significantly higher transfection rates compared to the polyplexes. Improvement in the\ntransfection efficiency was observed with the glycosylated HIV- and HSV-mimicking hybrid vectors,\nwhich also showed a safe biocompatibility profile based on the cytotoxicity and haemocompatibility\nassays. These glycosylated artificial viral envelope-based hybrid vectors could be used as safe gene\ndelivery systems with potential to become new compositions for efficient nonviral gene therapy....
The development of hybridoma technology for producing monoclonal antibodies (mAbs)\nby Kohler and Milstein (1975) counts as one of the major medical breakthroughs, opening up endless\npossibilities for research, diagnosis and for treatment of a whole variety of diseases. Therapeutic\nmAbs were introduced three decades ago. The first generation of therapeutic mAbs of murine\norigin showed high immunogenicity, which limited efficacy and was associated with severe infusion\nreactions. Subsequently chimeric, humanized, and fully human antibodies were introduced as\ntherapeutics, these mAbs were considerably less immunogenic. Unexpectedly humanized mAbs\ngenerally show similar immunogenicity as chimeric antibodies; based on sequence homology chimeric\nmAbs are sometimes more â??humanâ? than humanized mAbs. With the introduction of the regulatory\nconcept of similar biological medicines (biosimilars) a key concern is the similarity in terms of\nimmunogenicity of these biosimilars with their originators. This review focuses briefly on the\nmechanisms of induction of immunogenicity by biopharmaceuticals, mAbs in particular, in relation\nto the target of the immune system....
Dengue virus (DENV) threatens almost 70% of the worldâ??s population, with no effective\nvaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in\nthe infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin.................
Glucagon-like peptide-1 receptor (GLP-1R) agonists have emerged as treatment options\nfor type 2 diabetes mellitus (T2DM). Here, we designed a high-throughput GLP-1R extracellular\ndomain (ECD)-based system that enabled the screening of high-potency receptor-biased GLP-1R\nagonists demonstrating new pharmacological virtues. Firstly, six 12-mer peptides (termed PEP01-06),\nscreened from a large phage displayed peptide library were fused to the N-terminus of Exendin-4\n(29-39) to generate PEP07-12. By the use of four lysine-altered PEP07 (PEP13-16) as the starting\npoint, a series of fatty chain conjugates (PEP17-20) were synthesized and evaluated by in vitro\nGLP-1R-based cell assays. In addition, the acute and long-term in vivo effects on diet-induced\nobesity (DIO) mice were further evaluated. All four conjugates showed good receptor activation\nefficacy, and PEP20 was selected to undergo further assessment. Preclinical experiments in DIO\nmice demonstrated that PEP20 had significant insulinotropic activities and glucose-lowering abilities.\nMoreover, a prolonged antidiabetic effect of PEP20 was also observed by the hypoglycemic test in\nDIO mice. Furthermore, long-term treatment with PEP20 achieved beneficial effects on the food\nintake, weight gain, hemoglobin A1C (HbA1C) lowering activity, and glucose tolerance compared\nwith the control and was similar to the Liraglutide. In conclusion, PEP20, a GLP-1R ECD-biased\nagonist, may provide a novel therapeutic approach to T2DM....
The demand for reliable comparability studies of biosimilars grows with their increased market\nshare. These studies focus on physicochemical, structural, functional and clinical properties to ensure that\na biosimilar has no significant differences to the originator product and can be released into the market\nwithout extensive clinical trials. In the current study, Enbrel® (etanercept, the originator) and Altebrelâ?¢\n(the proposed biosimilar) underwent direct comparison. â??Bottom-upâ? mass spectrometric analysis\nwas used for primary sequence analysis, evaluation of N/O-glycosylation sites and quantification of\nmethionine oxidation. N/O-glycans were analyzed after permethylation derivatization and the effect of\nN-glycans on in-vitro functionality of etanercept was assayed. Three enzyme peptide mapping resulted\nin complete identification of the primary structure. It was confirmed that total ion chromatograms are\nvaluable datasets for the analysis of the primary structure of biodrugs. New N/O-glycan structures\nwere identified and all the N-glycans were quantified. Finally, investigation of the functional properties\nof N-deglycosylated and non-modified etanercept samples using surface plasmon resonance analysis\nand in-vitro bioassay showed that N-glycosylation has no significant effect on its in-vitro functionality.\nAnalysis of etanercept and its biosimilar, revealed a high similarity in terms of glycosylation, primary\nstructure and in-vitro functionality....
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