Publications by authors named "Janez Mravljak"

The excipient selection process plays a crucial role in biopharmaceutical formulation development to ensure the long-term stability of the drug product. Though there are numerous options approved by regulatory authorities, only a subset is commonly utilized. Previous research has proposed various stabilization mechanisms, including protein-excipient interactions.

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  • The study focuses on improving biopharmaceutical drug formulations by investigating various buffer systems for monoclonal antibodies (mAbs) to enhance protein stability.
  • While traditional buffers like histidine and phosphate are commonly used, the research shows that alternative buffers, particularly arginine/citrate and histidine/citrate, can significantly improve stability under stress conditions.
  • The results indicate that relying solely on conventional buffers can limit the effectiveness of biopharmaceutical formulations, as many alternatives demonstrate equal or better performance in maintaining protein integrity.
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Polysorbates, widely used excipients in drug formulations, present a stability challenge due to complex degradation processes. This study investigates the hydrolysis of polysorbate (PS) under temperature stress (50 °C), focusing on the impact of primary packaging materials (glass vs. plastic vials), buffers (histidine and acetic acid), counterions (chloride vs.

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A library of 31 butyrylcholinesterase (BChE) and cathepsin B (CatB) inhibitors was screened in vitro for inhibition of deoxyribonuclease I (DNase I). Compounds 22, 8 and 7 are among the most potent synthetic non-peptide DNase I inhibitors reported to date. Three 8-hydroxyquinoline analogues inhibited both DNase I and BChE with IC values below 35 μM and 50 nM, respectively, while two nitroxoline derivatives inhibited DNase I and Cat B endopeptidase activity with IC values below 60 and 20 μM.

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Comprehensive comparisons of similar lipid based drug delivery systems produced by different technologies are scarce. Spray drying and fluid bed layering technologies were compared with respect to the process and product characteristics of otherwise similar simvastatin loaded dry emulsion systems. Fluid bed layering provided higher process yield (83.

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Quinazolinones represent an important scaffold in medicinal chemistry with diverse biological activities. Here, two series of 2-substituted quinazolin-4(3)-ones were synthesized and evaluated for their antioxidant properties using three different methods, namely DPPH, ABTS and TEAC, to obtain key information about the structure-antioxidant activity relationships of a diverse set of substituents at position 2 of the main quinazolinone scaffold. Regarding the antioxidant activity, ABTS and TEAC assays were more sensitive and gave more reliable results than the DPPH assay.

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  • * The research focused on enhancing a known galectin-8 ligand by modifying its structure, resulting in improved affinity with a K value of 12 µM.
  • * The modified compound shows reasonable selectivity for galectin-8 compared to other galectins, making it a promising candidate for developing new ligands to study the protein's role in cellular and in-vivo contexts.
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Lectins are involved in a wide range of carbohydrate mediated recognition processes. Therefore, the availability of highly performant fluorescent tools tailored for lectin targeting and able to efficiently track events related to such key targets is in high demand. We report here on the synthesis of the glyco-BODIPYs 1 and 2, based on the efficient combination of a Heck-like cross coupling and a Knoevenagel condensation, which revealed efficient in addressing lectins.

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The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. Selective inhibition of its catalytic activities is therefore a viable approach for the treatment of these diseases.

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The immunoproteasome is a multicatalytic protease that is predominantly expressed in cells of hematopoietic origin. Its elevated expression has been associated with autoimmune diseases, various types of cancer, and inflammatory diseases. The development of immunoproteasome-selective inhibitors with non-peptidic scaffolds remains a challenging task.

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We synthesized and determined the antioxidant activity and distribution of a new cyanothiophene-based compound, -(3-cyano-4,5,6,7-tetrahydrobenzo[]thiophen-2-yl)-3,5-dihydroxybenzamide (SIM-53B), in intact stripped olive oil-in-water emulsion. The in vitro antioxidant properties of SIM-53B were evaluated and compared to those for Trolox and resveratrol. Addition of an emulsifier (Tween 20) creates a narrow region, the aqueous-oil interface, and the distribution of SIM-53B can be described by two partition constants: (between aqueous/interfacial regions) and (between oil/interfacial regions).

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  • Polysorbates are essential surfactants in biopharmaceuticals, but their degradation can lead to unwanted particle formation, a significant issue in the industry.
  • The study examined how commonly used buffers, specifically histidine chloride, affect polysorbate stability, revealing that histidine chloride accelerates degradation through ester hydrolysis.
  • Interestingly, therapeutic proteins can mitigate this degradation in many cases, highlighting the need for careful consideration of excipients to ensure compatibility in drug formulations.
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Proteins are prone to post-translational modifications at specific sites, which can affect their physicochemical properties, and consequently also their safety and efficacy. Sources of post-translational modifications include oxygen and reactive oxygen species. Additionally, catalytic amounts of Fe(II) or Cu(I) can promote increased activities of reactive oxygen species, and thus catalyse the production of particularly reactive hydroxyl radicals.

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The structural integrity, elasticity, and fluidity of lipid membranes are critical for cellular activities such as communication between cells, exocytosis, and endocytosis. Unsaturated lipids, the main components of biological membranes, are particularly susceptible to the oxidative attack of reactive oxygen species. The peroxidation of unsaturated lipids, in our case 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), induces the structural reorganization of the membrane.

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Formulation development is an essential part of any biopharmaceuticals development programme, and this will affect quality, safety and efficacy of the final drug product. The vast majority of biopharmaceuticals on the market are therapeutic proteins; however, these are less stable compared to conventional pharmaceuticals. To counter aggregation, denaturation and surface adsorption of proteins in solution, surfactants are added to the formulations; however, the choice of the best formulation is a challenge that is faced during formulation development.

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Polysorbates (PS) are the most common non-ionic surfactants used in protein formulations. Their degradation has been studied intensively in recent years. Ester bond hydrolysis is one of many pathways of PS degradation that can lead to accumulation of free fatty acids (FFAs) and particle formation.

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We present a novel route for the preparation of amino acid-derived cyclic imide dioxime derivatives. Readily accessible amino acids were conveniently converted to their corresponding cyclic imide dioximes in simple synthetic steps. The aim of this work was to describe and compare the iron-chelating and antioxidant properties of synthesized compounds in relation to their molecular structure, and in particular, which of those features are essential for iron(II)-chelating ability.

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The limited clinical efficacy of current symptomatic treatment and minute effect on progression of Alzheimer's disease has shifted the research focus from single targets towards multi-target-directed ligands. Here, a potent selective inhibitor of human butyrylcholinesterase was used as the starting point to develop a new series of multifunctional ligands. A focused library of derivatives was designed and synthesised that showed both butyrylcholinesterase inhibition and good antioxidant activity as determined by the DPPH assay.

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Insight into the microstructure of lyotropic liquid crystals (LCs) is of crucial importance for development of novel dermal delivery systems. Our aim was to evaluate the phase behaviour of dermally applicable LCs composed of isopropyl myristate/Tween 80/lecithin/water, along the dilution line, where phase transitions are predominantly driven by increased water content. Additionally, identification of LC temperature dependence is of great importance for skin application.

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DC-SIGN, an antigen-uptake receptor in dendritic cells (DCs), has a clear role in the immune response but, conversely, can also facilitate infection by providing entry of pathogens into DCs. The key action in both processes is internalization into acidic endosomes and lysosomes. Molecular probes that bind to DC-SIGN could thus provide a useful tool to study internalization and constitute potential antagonists against pathogens.

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A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties. Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives. The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which were employed in the virtual screening experiments of compound libraries and for the prediction of their antioxidant activity, with the goal of discovering novel compounds possessing antioxidant properties.

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Tremendous efforts have been dedicated to the development of effective therapeutics against Alzheimer's disease, which represents the most common debilitating neurodegenerative disease. Multifunctional agents are molecules designed to have simultaneous effects on different pathological processes. Such compounds represent an emerging strategy for the development of effective treatments against Alzheimer's disease.

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Background: The development of efficient drug delivery systems to transport therapeutics across barrier-forming cells remains a challenge. Recently it was shown that liposomes containing perifosine, a synthetic analog of lysophosphatidylcholine, efficiently deliver liposome encapsulated content across barrier-forming cells.

Methods: To elucidate the mechanism of the delivery, fluorescent and spin labeled analog of perifosine were synthesized and their transport from liposomes to the barrier-forming MDKC cells was measured.

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To study the release of liposome-associated drugs into hydrogels, we designed and synthesized two pH-sensitive rhodamine derivatives to use as model compounds of different lipophilicities. The dyes were fluorescent when in the free form released from liposomes into the chitosan hydrogel, but not when incorporated within liposomes. The effect of liposomal composition, surface charge and vesicle size on the release of those incorporated dyes was evaluated.

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New amphiphilic benzamidoxime, benzoxime, and aliphatic oxime derivatives of glycolipid mimetics were synthesized. The total antioxidant capacity of these amphiphilic derivatives was evaluated using DPPH assay. The observed antioxidant activity was the highest for benzamidoxime derivatives and glycolipid mimetics with two oxime functionalities, followed by benzoxime derivatives, glycolipid mimetics with one oxime group, and dimers of oxime.

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