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171.
Iwona Winiecka Paweł Jaworski Aleksander Paweł Mazurek Dorota Marszałek Anna Goldnik Daniel Sokulski 《Journal of peptide science》2016,22(2):106-115
In search for new drugs lowering arterial blood pressure, which could be applied in anti‐hypertensive therapy, research concerning agents blocking of renin‐angiotensin‐aldosteron system has been conducted. Despite many years of research conducted at many research centers around the world, aliskiren is the only one renin inhibitor, which is used up to now. Four novel potential renin inhibitors, having structure based on the peptide fragment 8–13 of human angiotensinogen, a natural substrate for renin, were designed and synthesized. All these inhibitors contain unnatural moieties that are derivatives of N‐methylleucyl‐β‐hydroxy‐γ‐amino acids at the P2‐P1' position: 4‐[N‐(N‐methylleucyl)‐amino]‐3‐hydroxy‐7‐(3‐nitroguanidino)‐heptanoic acid (AHGHA), 4‐[N‐(N‐methylleucyl)‐amino]‐3‐hydroxy‐5‐phenyl‐pentanoic acid (AHPPA) or 4‐[N‐(N‐methylleucyl)‐amino]‐8‐benzyloxycarbonylamino‐3‐hydroxyoctanoic acid (AAHOA). The previously listed synthetic β‐hydroxy‐γ‐amino acids constitute pseudodipeptidic units that correspond to the P1‐P1' position of the inhibitor molecule. An unnatural amino acid, 4‐methoxyphenylalanin (Phe(4‐OMe)), was introduced at the P3 position of the obtained compounds. Three of these compounds contain isoamylamide of 6‐aminohexanoic acid (ε‐Ahx‐Iaa) at the P2'‐P3' position. The proposed modifications of the selected human angiotensinogen fragment are intended to increase bioactivity, bioavailability, and stability of the inhibitor molecule in body fluids and tissues. The inhibitor Boc‐Phe(4‐OMe)‐MeLeu‐AHGHA‐OEt was obtained in the form of an ethyl ester. The hydrophobicity coefficient, expressed as log P varied between 3.95 and 8.17. In vitro renin inhibitory activity of all obtained compounds was contained within the range 10?6‐10?9 M. The compound Boc‐Phe(4‐OMe)‐MeLeu‐AHPPA‐Ahx‐Iaa proved to be the most active (IC50 = 1.05 × 10?9 M). The compounds Boc‐Phe(4‐OMe)‐MeLeu‐AHGHA‐Ahx‐Iaa and Boc‐Phe(4‐OMe)‐MeLeu‐AHPPA‐Ahx‐Iaa are resistant to chymotrypsin. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd. 相似文献
172.
173.
Przybyło M Martuszewska D Pocheć E Hoja-Łukowicz D Lityńska A 《Biochimica et biophysica acta》2007,1770(9):1427-1435
The common structural alterations in the cell-surface glycoproteins concern the highly elevated expression of tri- and tetra-antennary beta1-6-N-acetylglucosamine (beta1-6 GlcNAc) bearing N-glycans, which are recognised by Phaseolus vulgaris agglutinin (PHA-L). In this report we identified proteins bearing beta1-6 GlcNAc branched N-glycans in three human melanoma cell lines: WM35--from the primary tumour site, as well as WM239 and WM9 from different metastatic sites: the skin and the lymph node, respectively, by tandem mass spectrometry (MS/MS) on PHA-L agarose bound material, followed by immunochemical identification. Our results show that melanoma cell lines differ from each other in the number of N-glycoproteins bearing beta1-6 GlcNAc branched oligosaccharides. Among identified proteins the largest group consists of integrin subunits. In addition, L1-CAM, Mac-2 binding protein, melanoma cell adhesion molecule, intercellular adhesion molecule, melanoma associated antigen, tumour rejection antigen-1, melanoma-associated chondroitin sulfate proteoglycan 4 and lysosome-associated membrane protein (LAMP-1) were found. It was indicated that WM35 cell line showed the lowest number of proteins possessing beta1-6 GlcNAc branched N-glycans in comparison to metastatic WM9 and WM239 cell lines. Our data suggest that changes in the number of proteins being a substrate for GlcNAc-TV are better correlated with melanoma development and progression than with expression of cell adhesion molecules. 相似文献
174.
Jazowiecka-Rakus J Jarosz M Kozłowska D Sochanik A Szala S 《Acta biochimica Polonica》2007,54(1):125-133
Growth of tumors is strongly dependent upon supply of nutrients and oxygen by de novo formed blood vessels. Inhibiting angiogenesis suppresses growth of primary tumors as well and affects development of metastases. We demonstrate that recombinant MBP/vasostatin fusion protein inhibits proliferation of endothelial cells in vitro. The therapeutic usefulness of such intratumorally delivered recombinant protein was then assessed by investigating its ability to inhibit growth of experimental murine melanomas. In the model of B16-F10 melanoma the MBP/vasostatin construct significantly delayed tumor growth and prolonged survival of treated mice. A combination therapy involving MBP/vasostatin construct and cyclophosphamide was even more effective and led to further inhibition of the tumor growth and extended survival. We show that such combination might be useful in the clinical setting, especially to treat tumors which have already formed microvessel networks. 相似文献
175.
Krzysztof Tatoj Adam M. Ćmiel Dorota Kwaśna Anna M. Lipińska Katarzyna Zając Tadeusz Zając 《Biodiversity and Conservation》2017,26(5):1217-1224
Large freshwater mussels (Unionoida) are declining throughout the world. The European bitterling Rhodeus amarus (Bloch, 1782) female spawns its eggs inside the unionids’ shells, where fertilisation and further embryonic development take place; thus its reproduction depends fully on the presence of large freshwater mussels. Unio crassus, previously regarded as one of the most numerous unionids in Europe, is now listed in the IUCN Red Data List as being globally endangered. Despite its previous prevalence, it was never reported as a host for the bitterling. A large population of U. crassus was studied in small river at the ?wi?tokrzyskie Mts (Poland), where also electrofishing was conducted. In each bitterling territory located on the study plots, we found individuals of U. crassus, with the bitterling eggs or larvae developing on mussel’s gills. That proves that this species can be also used by the bitterling for reproduction. We suggest that this relationship has not been reported to date due to the mussels’ rarity and ongoing decline. However, it is also possible that the endangered mussel is a novel host for the bitterling, which is expanding its range throughout Europe. 相似文献
176.
Kamil J. Kuder Dorota Łażewska Maria Kaleta Gniewomir Latacz Tim Kottke Agnieszka Olejarz Tadeusz Karcz Andrzej Fruziński Katarzyna Szczepańska Janina Karolak-Wojciechowska Holger Stark Katarzyna Kieć-Kononowicz 《Bioorganic & medicinal chemistry》2017,25(10):2701-2712
As a continuation of our search for novel histamine H3 receptor ligands a series of twenty new tert-amyl phenoxyalkylamine derivatives (2–21) was synthesized. Compounds of four to eight carbon atoms spacer alkyl chain were evaluated on their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for pentyl derivatives 6–8 (Ki = 8.8–23.4 nM range) and among them piperidine derivative 6 with Ki = 8.8 nM. Structures 6, 7 were also classified as antagonists in cAMP accumulation assay (with EC50 = 157 and 164 nM, respectively). Moreover, new compounds were also evaluated for anticonvulsant activity in Antiepileptic Screening Program (ASP) at National Institute of Neurological Disorders and Stroke (USA). Seven compounds (2–4, 9, 11, 12 and 20) showed anticonvulsant activity at maximal electroshock (MES) test in the dose of 30 mg/kg at 0.5 h. In the subcutaneous pentetrazole (scMET) test compound 4 showed protection at 100 and 300 mg/kg dose at mice, however compounds showed high neurotoxicity in rotarod test at used doses. Also, molecular modeling studies were undertaken, to explain affinity of compounds at hH3R (taking into the consideration X-ray analysis of compound 18). In order to estimate “drug-likeness” of selected compounds in silico and experimental evaluation of lipophilicity, metabolic stability and cytotoxicity was performed. 相似文献
177.
High Quality Independent From a Donor: Human Amniotic Fluid Derived Stem Cells—A Practical Analysis Based on 165 Clinical Cases
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178.
A shortcut method for evaluation of protein deposition onto the membrane surface in crossflow ultrafiltration
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In this study, a procedure for quantifying the surface deposition of proteins in crossflow ultrafiltration has been developed. The procedure consists of determining the protein adsorption behavior onto the membrane surface from a few dynamic measurements performed in a nonfiltration and a filtration mode, and evaluating the concentration polarization (CP) layer thickness based on the adsorption data. To predict the interdependence between the protein adsorption and CP, a simplified mathematical model has been formulated. The model was used to assess the protein adsorption and thus yield reduction in the ultrafiltration process at different protein concentration in the solution. As a case study, ultrafiltration of aqueous solutions of BSA and lysozyme (LYZ) was examined on a polyethersulfone membrane with the molecular weight cutoff of 10 or 100 kDa. The protein concentration in the solutions varied within a relatively low concentration range, i.e. below 10 mg mL?1, characteristic for solvent exchange between sequential operations of protein purification by chromatography and extraction. Both proteins markedly differed in the mechanism of surface deposition; for BSA hydrophobic interactions were suggested to be dominant, whereas in case of LYZ electrostatic interactions contributed the most to the deposition mechanism. The effect of additives of the protein solutions, i.e. inorganic salts, PEG, and urea depended on the adsorption mechanism and was also specific for each protein. Nevertheless, the proposed procedure performed well in the evaluation of surface deposition and yield reduction, regardless of the protein type and its solvent environment. 相似文献
179.
Handzlik J Maciag D Kubacka M Mogilski S Filipek B Stadnicka K Kieć-Kononowicz K 《Bioorganic & medicinal chemistry》2008,16(11):5982-5998
In the search for new antiarrhythmic agents, some active 2-methoxyphenylpiperazine derivatives of phenytoin were obtained as a chemical modification of compound AZ-99 (3-ethyl-1-[2-hydroxy-3-(4-phenylpiperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenylimidazolidine). These compounds possessed structural properties similar to those of alpha(1)-adrenoceptor antagonists. In the present study, the affinities of the 2-methoxyphenylpiperazine derivatives (1a-3a) for alpha(1)- and alpha(2)-adrenoceptors were evaluated using radioligand ([(3)H]prazosin, [(3)H]clonidine) binding assays. In the next step, a new series of phenylpiperazine derivatives of phenytoin (4a-16a) containing 2-methoxyphenyl-, 2-ethoxyphenyl-, 2-pyridyl- or 2-furoylpiperazine moiety, as well as, various ester or alkyl substituents at 3-position of hydantoin ring were synthesized. The newly synthesized compounds were tested for their affinity to alpha(1)- and alpha(2)-adrenoceptors. They have shown affinities for alpha(1)-adrenoceptors at nanomolar to submicromolar range. Some compounds were moderately selective ligands of alpha(1)-adrenoceptors. Selected compounds (3a-5a, 7a, 13a, 14a) were also evaluated for their alpha(1)-adrenoceptor antagonistic properties in functional bioassays. A SAR study indicated that the most active compounds contain 2-alkoxyphenylpiperazine moieties and methyl or 2-methylpropionate substituent at 3-N position in hydantoin. The exchange of 2-alkoxyphenyl moiety into 2-furoyl or 2-pyridyl group significantly decreased affinities for alpha(1)-adrenoceptors. Molecular modelling results obtained using conformational analysis CONFLEX and PM5 method for geometry optimization, allowed for comparison of the spatial properties of tested compounds with pharmacophore model created by Barbaro et al. for the ideal alpha(1)-adrenoceptor antagonist. 相似文献
180.
Łukasz Jaremko Mariusz Jaremko Paweł Pasikowski Marek Cebrat Piotr Stefanowicz Marek Lisowski Jolanta Artym Michał Zimecki Igor Zhukov Zbigniew Szewczuk 《Biopolymers》2009,91(6):423-431
Recently, ubiquitin was suggested as a promising anti‐inflammatory protein therapeutic. We found that a peptide fragment corresponding to the ubiquitin50–59 sequence (LEDGRTLSDY) possessed the immunosuppressive activity comparable with that of ubiquitin. CD and NMR spectroscopies were used to determine the conformational preferences of LEDGRTLSDY in solution. The peptide mixture, obtained by pepsin digestion of ubiquitin, was even more potent than the intact protein. Although the peptide exhibited a well‐defined conformation in methanol, its structure was distinct from the corresponding 50–59 fragment in the native ubiquitin molecule. © 2009 Wiley Periodicals, Inc. Biopolymers 91: 423–431, 2009. This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com 相似文献