Elevated expression of the immunoproteasome has been associated with autoimmune diseases, inflammatory diseases, and various types of cancer. Selective inhibitors of the immunoproteasome are not only scarce, but also almost entirely restricted to peptide-based compounds. Herein, we describe nonpeptidic reversible inhibitors that selectively block the chymotrypsin-like (ß5i) subunit of the human immunoproteasome in the low micromolar range. The most potent of the reversibly acting compounds were then converted into covalent, irreversible, nonpeptidic inhibitors that retained selectivity for the ß5i subunit. In addition, these inhibitors discriminate between the immunoproteasome and the constitutive proteasome in cell-based assays. Along with their lack of cytotoxicity, these data point to these nonpeptidic compounds being suitable for further investigation as ß5i-selective probes for possible application in noncancer diseases related to the immunoproteasome.
COBISS.SI-ID: 4050545
Alzheimer’s disease (AD) is characterized by severe basal forebrain cholinergic deficit, which results in progressive and chronic deterioration of memory and cognitive functions. Similar to acetylcholinesterase, butyrylcholinesterase (BChE) contributes to the termination of cholinergic neurotransmission. Its enzymatic activity increases with the disease progression, thus classifying BChE as a viable therapeutic target in advanced AD. Potent, selective and reversible human BChE inhibitors were developed. The solved crystal structure of human BChE in complex with the most potent inhibitor reveals its binding mode and provides the molecular basis of its low nanomolar potency. Additionally, this compound is noncytotoxic and has neuroprotective properties. Furthermore, this inhibitor moderately crosses the blood-brain barrier and improves memory, cognitive functions and learning abilities of mice in a model of the cholinergic deficit that characterizes AD, without producing acute cholinergic adverse effects. Our study provides an advanced lead compound for developing drugs for alleviating symptoms caused by cholinergic hypofunction in advanced AD.
COBISS.SI-ID: 4263537
Dipeptidyl peptidase-4 (DPP-4) is a serine protease that is involved in the inactivation of glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), having in this way a profound influence on glucose metabolism. During organ damage, stromal and endothelial cells produce a chemokine known as stromal cell-derived factor-1 (SDF-1), a powerful chemoattractant of stem/progenitor cells. SDF-1 binds to a specific α-chemokine receptor and can be degraded by proteases, including matrix DPP-4/CD26, presented in the circulation, or activated in injured tissues. Since DPP-4 degrades SDF-1, especially after myocardial infarction, inhibition of circulating proteases could maintain the optimal endogenous SDF-1 concentration and may enhance homing of endothelial progenitor cells. Since protection against the overactivity of proteases is important for restoring cardiac function and repair after myocardial damage, necrosis and apoptosis, we propose that administration of a DPP-4 inhibitor may also be beneficial following myocardial infarction by the prevention of cleavage of stem cell chemoattractant cytokine SDF-1.
COBISS.SI-ID: 4132209
Bacterial DNA gyrase is a well-known and validated target in the design of antibacterial drugs. However, inhibitors of its ATP binding subunit, DNA gyrase B (GyrB), have so far not reached clinical use. In the present study, three different series of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides were designed and prepared as potential DNA gyrase B inhibitors. The IC50 values of compounds on DNA gyrase from Escherichia coli were in the low micromolar range, with the best compound, (4-(4,5-dibromo-1H-pyrrole-2-carboxamido)benzoyl)glycine (6a), displaying an IC50 of 450 nM. For this compound a high-resolution crystal structure in complex with E. coli DNA gyrase B was obtained, revealing details of its binding mode within the active site. The binding affinities of three compounds with GyrB were additionally evaluated by surface plasmon resonance and the results were in good agreement with the determined enzymatic activities. For the most promising compounds the inhibitory activities against DNA gyrase from Staphylococcus aureus and topoisomerases IV from E. coli and S. aureus were determined. Antibacterial activities of the most potent compounds of each series were evaluated against two Gram-positive and two Gram-negative bacterial strains. The results obtained in this study provide valuable information on the binding mode and structure-activity relationship of N-phenyl-4,5-dibromopyrrolamides and N-phenylindolamides as promising classes of ATP competitive GyrB inhibitors.
COBISS.SI-ID: 3888753
Bisphenol A (BPA) and its analogues (BPF and BPAF) are a class of industrial chemicals that are proven to elicit endocrine disrupting effects, thus it is important to reduce their concentrations in effluent streams as much as possible. In this study, a simple and highly active glass fiber-supported TiO2 photocatalyst was synthesized and applied in a UV-irradiated three-phase batch and continuous stirred-tank reactor (CSTR) for removal of toxicity and estrogenicity of water dissolved bisphenols. Bioassays of photocatalytically treated aqueous samples showed no estrogenic activity and complete removal of toxicity after 4 h of illumination, which was in accordance with high mineralization extent of bisphenols and their reaction derivatives. The photocatalytic examination of bisphenolic compounds revealed considerably higher stability of BPAF under UV light irradiation, due to two CF3 groups attached to the central C atom. Moreover, these fluorinated groups were responsible for markedly higher toxicity of BPAF to crustaceans D. magna in comparison to non-halogenated BPA and BPF, which manifested daphnids as excellent aquatic species for sensing fluorinated (halogenated) bisphenolic compounds. In addition, photocatalytic oxidation of bisphenol analogues in CSTR demonstrated feasibility of using the immobilized TiO2 photocatalyst in continuous-flow light-assisted water purification systems. Detailed characterization of fresh and used photocatalysts confirmed substantial changes in active material structure. However, the corresponding impact on photocatalyst stability was found insignificant.
COBISS.SI-ID: 3969137