Butyrylcholinesterase (BChE) is regarded as a promising drug target as its levels and activity significantly increase in the late stages of Alzheimer's disease. To discover novel BChE inhibitors, we used a hierarchical virtual screening protocol followed by biochemical evaluation of 40 highest scoring hit compounds. Three of the compounds identified showed significant inhibitory activities against BChE. The compound with the highest affinity (21.7 nM) was resynthesized, the two enantiomers were separated and some ten times better affinity was determined for (+) enantiomere. 3D structure of the complex with human butyrylcholinesterase was solved by x-ray crystallography which provided clues for further optimization. The new compound inhibits self-induced aggregation of beta-amyloid (61.7% at 10 mM) and protects SH-SYSY cells against amyloid toxicity.
COBISS.SI-ID: 3713393
Nine organoruthenium complexes with azole antifungal agents (L) clotrimazole (ctz), tioconazole (tcz), and miconazole (mcz) with the general formulas [(η6-p-cymene)RuCl2(L)], [(η6-p-cymene)RuCl(L)2]Cl, and [(η6-p-cymene)Ru(L)3](PF6)2 were prepared and characterized by NMR, HRMS, IR, UV–vis, and X-ray crystallography. Herein, we report the first crystal structure of a tioconazole metal complex as well as the structure of the tioconazole ligand itself and the bis-clotrimazole complex as a hexafluorophosphate salt. The complexes possess a pseudooctahedral geometry typical for organoruthenium(II) compounds where half of the coordination sites are occupied by the π-bonded arene ligand p-cymene while the remaining sites are occupied by either the chlorido ligands and/or the azole ligands. The stability of the compounds in dmso solution was studied by NMR spectroscopy. The biological activity of all nine complexes and the ruthenium precursor against the fungus Culvularia lunata was evaluated. The complexes showed antifungal activity at low millimolar concentrations, where the activity decreased with the increasing number of ligands. However at 0.5 mM concentrations all tris-azole complexes statistically significantly reduced the radial growth rate, and also at 0.01 mM concentrations the monoazole complexes showed statistically significant effects. Mcz and its complexes were also tested against the human parasite Schistosoma mansoni and revealed schistocidal activity at 10–100 μg/mL in vitro.
COBISS.SI-ID: 1695791
Environments with high concentrations of salt suppress the growth and survival of most eukaryotic organisms. Some species, among which are also fungi, are particularly successful in adaptation to such extreme environments on the level of cell physiology and morphology. As part of a programme, the strategy of adaptation of the obligately halophilic fungus Wallemia ichthyophaga to the extremely high concentrations of salt in the environment was studied at the level of cations accumulation and synthesis of compatible solutes. This species is the most unique among the fungi from saline environments – it requires substantial amounts of salts for growth and grows better in the presence of high concentrations of salts rather than sugars. Its physiology was completely unknown, so uncovering the mechanisms of its adaptation significantly contributed to the advance in science of this field. Thus W. ichthyophaga could represent a new model organism for the study of true halophilic, not only halotolerant, organisms. This knowledge is also essential for the biotechnological applications such as the development of salt- resistant plants or industrially important yeast. In the study, the collaboration of two foreign research groups, which are among the leading of the field, brought to the publication of the article in a respectable journal, which falls in the first quarter of the corresponding field of SCI.
COBISS.SI-ID: 3005263
Discovery of the extremely halotolerant and adaptable fungus Hortaea werneckii and the obligate halophile Wallemia ichthyophaga introduced two new model organisms into studies on the mechanisms of salt tolerance in eukaryotes.Recently, in collaboration with BGI Genomics Institute Shenzhen, China and Canada's Michael Smith Genome Sciences Centre, Vancouver, Canada, the whole genomes of H.werneckii and W.ichthyophaga were sequences and published in 2013 in PlosOne and BMC Genomics respectively. Review article in Frontiers in Microbiology is the first examle of comparative analysis of genomes of halotolerant/halophilic fungi. We addressed differences that have been revealed from analysis of sequenced genomes of halotolerant H.werneckii and halophilic W.ichthyophaga. The most striking characteristics associated with H. werneckii are the large genetic redundancy, the expansion of genes encoding metal cation transporters, and a relatively recent whole genome duplication. In contrast, the genome of W. ichthyophaga is very compact, as less than 5000 protein-coding genes are predicted, which cover almost three quarters of the sequence. Importantly, there has been a significant increase in their hydrophobins, cell-wall proteins that have multiple cellular functions. Our previous studies and analysis of genomes have revealed the novel and intricate molecular mechanisms used by these fungi to combat high salt concentrations, which differ in many aspects between the extremely halotolerant H. werneckii and the halophilic W. ichthyophaga. Specifically, the high osmolarity glycerol signaling pathway that is important for sensing and responding to increased salt concentrations was compared between H. werneckii and W. ichthyophaga. In both of these fungi, the key signaling components are conserved, but there are structural and regulation differences between these pathways in H. werneckii and W. ichthyophaga.
COBISS.SI-ID: 3130191
We evaluated for the first time the influence of genetic variability in translesion polymerases REV1 and REV3L on the outcome of cisplatin treatment. ln total, 139 malignant mesothelioma patients were genotyped for seven tag SNPs in REV1 and REV3L. Logistic regression and Cox regression were used to assess the influence of SNPs on treatment outcome. Polymorphic REV1 rs3087403 allele and REV1 TGT haplotype were associated with increased risk for leukopenia (p = 0.013 and p = 0.047, respectively) and neutropenia (p = 0.048 and p = 0.024, respectively). REV3L rs465646, rs462779 and REV3L CCGG haplotype were significantly associated with longer overall survival (p = 0.007, P = 0.022 and p = 0.013, respectively). Our results suggest for the first time that REV1 and REV3L SNPs might serve as potential predictive markers of outcome of cisplatin-based chemotherapy.
COBISS.SI-ID: 31396313