Publications by authors named "Justyna Fraczyk"

32 Publications

1,3,5-Triazine Nitrogen Mustards with Different Peptide Group as Innovative Candidates for AChE and BACE1 Inhibitors.

Molecules 2021 Jun 28;26(13). Epub 2021 Jun 28.

Department of Organic Chemistry, Medical University, Mickiewicza Street 2a, 15-222 Białystok, Poland.

A series of new analogs of nitrogen mustards (-) containing the 1,3,5-triazine ring substituted with dipeptide residue were synthesized and evaluated for the inhibition of both acetylcholinesterase (AChE) and -secretase (BACE1) enzymes. The AChE inhibitory activity studies were carried out using Ellman's colorimetric method, and the BACE1 inhibitory activity studies were carried out using fluorescence resonance energy transfer (FRET). All compounds displayed considerable AChE and BACE1 inhibition. The most active against both AChE and BACE1 enzymes were compounds and , with an inhibitory concentration of AChE IC = 0.051 µM; 0.055 µM and BACE1 IC = 9.00 µM; 11.09 µM, respectively.
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http://dx.doi.org/10.3390/molecules26133942DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8271926PMC
June 2021

Chemical Modification as a Method of Improving Biocompatibility of Carbon Nonwovens.

Materials (Basel) 2021 Jun 10;14(12). Epub 2021 Jun 10.

Łukasiewicz Research Network-Textile Research Institute, Brzezińska 5/15, 92-103 Lodz, Poland.

It was shown that carbon nonwoven fabrics obtained from polyacrylonitrile fibers (PAN) by thermal conversion may be modified on the surface in order to improve their biological compatibility and cellular response, which is particularly important in the regeneration of bone or cartilage tissue. Surface functionalization of carbon nonwovens containing C-C double bonds was carried out using in situ generated diazonium salts derived from aromatic amines containing both electron-acceptor and electron-donor substituents. It was shown that the modification method characteristic for materials containing aromatic structures may be successfully applied to the functionalization of carbon materials. The effectiveness of the surface modification of carbon nonwoven fabrics was confirmed by the FTIR method using an ATR device. The proposed approach allows the incorporation of various functional groups on the nonwovens' surface, which affects the morphology of fibers as well as their physicochemical properties (wettability). The introduction of a carboxyl group on the surface of nonwoven fabrics, in a reaction with 4-aminobenzoic acid, became a starting point for further modifications necessary for the attachment of RGD-type peptides facilitating cell adhesion to the surface of materials. The surface modification reduced the wettability () of the carbon nonwoven by about 50%. The surface free energy (SFE) in the chemically modified and reference nonwovens remained similar, with the surface modification causing an increase in the polar component (ɣ). The modification of the fiber surface was heterogeneous in nature; however, it provided an attractive site of cell-materials interaction by contacting them to the fiber surface, which supports the adhesion process.
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http://dx.doi.org/10.3390/ma14123198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230386PMC
June 2021

N-Methylated Analogs of hIAPP Fragments 18-22, 23-27, 33-37 Inhibit Aggregation of the Amyloidogenic Core of the Hormone.

Chem Biodivers 2021 Jan 17;18(1):e2000842. Epub 2020 Dec 17.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland.

Amylin (hIAPP) aggregation leads to the formation of insoluble deposits and is one of the factors in the development of type II diabetes. The aim of this research was to find N-methylated analogs of the aggregating amylin fragments 18-22, 23-27, and 33-37, which would not themselves be susceptible to aggregation and would inhibit the aggregation of the amyloidogenic cores of the hormone. None of the analogs of fragment 18-22 containing one or two N-methylated amino acid residues showed any tendency to aggregate. Only the peptide H-F(N-Me)GA(N-Me) IL-OH (6) derived from the 23-27 hIAPP hot spot did not form fibrous structures. All analogs of the 33-37 amylin fragment were characterized by the ability to form aggregates, despite the presence of N-methylated amino acids in their structures. N-Methylated peptides 1-5 demonstrated inhibitory properties against the aggregation of fragment 18-22. Aggregation of the amyloidogenic core of 23-27 was significantly inhibited by N-methylated peptides 1-3 derived from the (18-22) H-HSSNN-OH fragment and by the H-F(N-Me)GA(N-Me)IL-OH (6) fragment derived from the 23-27 amylin hot spot. Fragment (33-37) H-GSNTY-NH was found to be inhibited in the presence of N-methylated peptides 1-3 derived from the 18-22 fragment and by the double methylated peptide H-F(N-Me)GA(N-Me)IL-OH (6). Research on the possibility of using N-methylated analogs of amyloidogenic amylin cores as inhibitors of hormone aggregation is ongoing, with a focus on finding the minimum concentration of N-methylated peptides capable of inhibiting the aggregation of hIAPP hot spots.
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http://dx.doi.org/10.1002/cbdv.202000842DOI Listing
January 2021

New Human Islet Amyloid Polypeptide Fragments Susceptible to Aggregation.

Chem Biodivers 2020 Sep 8;17(9):e2000501. Epub 2020 Sep 8.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, Lodz, 90-924, Poland.

Human Islet Amyloid Polypeptide (hIAPP) plays a key role in the pathogenesis of type II diabetes. The aim of this research was to search for new amyloidogenic fragments of hIAPP. An initial attempt to predict the amyloidogenic cores of polypeptides/proteins using five different computer programs did not provide conclusive results. Therefore, we synthesized hIAPP fragments covering the entire hormone. The fragments were assessed for their aggregation ability, using recommended methods to search for the amyloidogenic fragments of the polypeptides/proteins. It was found that fragments (18-22) H-HSSNN-OH and (33-37) H-GSNTY-NH aggregate and form stable amyloid-like structures. Both of these fragments have a much higher antiproliferative activity relative to the RIN-5F cell compared to the (23-27) H-FGAIL-OH fragment widely regarded as the amyloidogenic core of amylin. The analog of (33-37) H-GSNTY-NH containing a free carboxy group on the C-terminal amino acid (H-GSNTY-OH) does not have amyloidogenic properties and can therefore be considered as a potential inhibitor of amylin aggregation. Research on the use of non-aggregating amylin fragments as potential hormone aggregation inhibitors is ongoing.
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http://dx.doi.org/10.1002/cbdv.202000501DOI Listing
September 2020

Conjugates of Chitosan and Calcium Alginate with Oligoproline and Oligohydroxyproline Derivatives for Potential Use in Regenerative Medicine.

Materials (Basel) 2020 Jul 10;13(14). Epub 2020 Jul 10.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

New materials that are as similar as possible in terms of structure and biology to the extracellular matrix (external environment) of cells are of great interest for regenerative medicine. Oligoproline and oligohydroxyproline derivatives (peptides -) are potential mimetics of collagen fragments. Peptides - have been shown to be similar to the model collagen fragment (H-Gly-Hyp-Pro-Ala-Hyp-Pro-OH, ) in terms of both their spatial structure and biological activity. In this study, peptides - were covalently bound to nonwovens based on chitosan and calcium alginate. Incorporation of the peptides was confirmed by Fourier transform -infrared (FT-IR) and zeta potential measurements. Biological studies (cell metabolic activity by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) test and Live/Dead assay) proved that the obtained peptide-polysaccharide conjugates were not toxic to the endothelial cell line EA.hy 926. In many cases, the conjugates had a highly affirmative influence on cell proliferation. The results of this study show that conjugates of chitosan and calcium alginate with oligoproline and oligohydroxyproline derivatives have potential for use in regenerative medicine.
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http://dx.doi.org/10.3390/ma13143079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412561PMC
July 2020

Biological Activity of Hydrophilic Extract of Grown on Post-Fermentation Leachate from a Biogas Plant Supplied with Stillage and Maize Silage.

Molecules 2020 Apr 14;25(8). Epub 2020 Apr 14.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

Algae are employed commonly in cosmetics, food and pharmaceuticals, as well as in feed production and biorefinery processes. In this study, post-fermentation leachate from a biogas plant which exploits stillage and maize silage was utilized as a culture medium for . The content of polyphenols in hydrophilic extracts of the biomass was determined, and the extracts were evaluated for their antioxidant activity (DPPH assay), antibacterial activity (against , , , ) and antifungal activity (against , , ). The use of the post-fermentation leachate was not found to affect the biological activity of the microalgae. The aqueous extract of biomass was also observed to exhibit activity against nematodes. The results of this study suggest that biomass cultured on post-fermentation leachate from a biogas plant can be successfully employed as a source of natural antioxidants, food supplements, feed, natural antibacterial and antifungal compounds, as well as in natural methods of plant protection.
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http://dx.doi.org/10.3390/molecules25081790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7221910PMC
April 2020

Conjugates of Copper Alginate with Arginine-Glycine-Aspartic Acid (RGD) for Potential Use in Regenerative Medicine.

Materials (Basel) 2020 Jan 11;13(2). Epub 2020 Jan 11.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

Current restrictions on the use of antibiotics, associated with increases in bacterial resistance, require new solutions, including materials with antibacterial properties. In this study, copper alginate fibers obtained using the classic wet method were used to make nonwovens which were modified with arginine-glycine-aspartic acid (RGD) derivatives. Stable polysaccharide-peptide conjugates formed by coupling with 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TosO), and materials with physically embedded RGD derivatives, were obtained. The materials were found to be characterized by very high antibacterial activity against and . Cytotoxicity studies confirmed that the materials are not cytotoxic. Copper alginate conjugates with RGD peptides have strong potential for use in regenerative medicine, due to their biocompatibility and innate antibacterial activity.
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http://dx.doi.org/10.3390/ma13020337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013949PMC
January 2020

Insulin Hot-Spot Analogs Formed with -Methylated Amino Acid Residues Inhibit Aggregation of Native Hormone.

Molecules 2019 Oct 15;24(20). Epub 2019 Oct 15.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

In this study, -methylated analogs of hot-spots of insulin were designed and synthesized, in the expectation that they would inhibit the aggregation of both insulin hot-spots and the entire hormone. Synthesis of insulin "amyloidogenic" analogs containing -methylated amino acid residues was performed by microwave-assisted solid phase according to the Fmoc/tert-Bu strategy. As a coupling reagent 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TosO) was used. Three independent methods were applied in aggregation studies of the complexes of insulin with its -methylated peptides. Additionally, circular dichroism (CD) measurements were used to confirm that aggregation processes did not occur in the presence of the -methylated analogs of hot-spot insulin fragments, and that insulin retains its native conformation. Of the seven -methylated analogs of the A- and B-chain hot-spots of insulin, six inhibited insulin aggregation (peptides and -). All tested peptides were found to have a lower ability to inhibit the aggregation of insulin hot-spots compared to the capability to inhibit native hormone aggregation.
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http://dx.doi.org/10.3390/molecules24203706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832904PMC
October 2019

Fibrous Aggregates of Short Peptides Containing Two Distinct Aromatic Amino Acid Residues.

Chem Biodivers 2019 Nov 25;16(11):e1900339. Epub 2019 Oct 25.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland.

The aim of the study was the assessment of the ability of short peptides to form aggregates under physiological conditions. The dipeptides studied were derived from different aromatic amino acids (heteroaromatic peptides). Tripeptides were obtained from two distinct aromatic amino acids and cysteine or methionine residue in the C-terminal, N-terminal, or central position. The ability of the peptides to form fibrous aggregates under physiological conditions was evaluated using three independent methods: the Congo Red assay, the Thioflavin T assay, and microscopic examinations using normal and polarized light. Materials potentially useful for regenerative medicine were selected based on their cytotoxicity to the endothelial cell line EA.hy 926 and physicochemical properties of films formed by peptides. The required parameters of biocompatibility were fulfilled by H-PheCysTrp-OH, H-PheCysTyr-OH, H-PheTyrMet-OH, and H-TrpTyr-OH.
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http://dx.doi.org/10.1002/cbdv.201900339DOI Listing
November 2019

Synthesis and cellular effects of novel 1,3,5-triazine derivatives in DLD and Ht-29 human colon cancer cell lines.

Invest New Drugs 2020 08 13;38(4):990-1002. Epub 2019 Sep 13.

Department of Organic Chemistry, Medical University of Bialystok, Białystok, Poland.

This study provides new information on the cellular effects of 1,3,5-triazine nitrogen mustards with different peptide groups in DLD and Ht-29 human colon cancer cell lines. A novel series of 2,4,6-trisubstituted 1,3,5-triazine derivatives bearing 2-chloroethyl and oligopeptide moieties was designed and synthesized. The most cytotoxic derivative was triazine with an Ala-Ala-OMe substituent on the ring (compound 7b). This compound induced time- and dose-dependent cytotoxicity in the DLD-1 and HT-29 colon cancer cell lines. The triazine derivative furthermore induced apoptosis through intracellular signaling pathway attenuation. Compound 7b may be a candidate for further evaluation as a chemotherapeutic agent against colorectal cancer.
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http://dx.doi.org/10.1007/s10637-019-00838-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7340680PMC
August 2020

Search for New Aggregable Fragments of Human Insulin.

Molecules 2019 Apr 23;24(8). Epub 2019 Apr 23.

Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

In this study, three independent methods were used to identify short fragment of both chains of human insulin which are prone for aggregation. In addition, circular dichroism (CD) research was conducted to understand the progress of aggregation over time. The insulin fragments (deca- and pepta-peptides) were obtained by solid-phase synthesis using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium toluene-4-sulfonate (DMT/NMM/TosO) as a coupling reagent. Systematic studies allowed identification of the new fragments, expected to be engaged in triggering aggregation of the entire structure of human insulin under physiological conditions. It was found that the aggregation process occurs through various structural conformers and may favor the formation of a fibrous structure of aggregate.
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http://dx.doi.org/10.3390/molecules24081600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514721PMC
April 2019

-Lipidated Amino Acids and Peptides Immobilizedon Cellulose Able to Split Amide Bonds.

Materials (Basel) 2019 Feb 14;12(4). Epub 2019 Feb 14.

Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

N-lipidated short peptides and amino acids immobilized on the cellulose were used ascatalysts cleaved amide bonds under biomimetic conditions. In order to select catalytically mostactive derivatives a library of 156 N-lipidated amino acids, dipeptides and tripeptides immobilizedon cellulose was obtained. The library was synthesized from serine, histidine and glutamic acidpeptides N-acylated with heptanoic, octanoic, hexadecanoic and (E)-octadec-9-enoic acids.Catalytic efficiency was monitored by spectrophotometric determination of p-nitroaniline formedby the hydrolysis of a 0.1 M solution of Z-Leu-NP. The most active 8 structures contained tripeptidefragment with 1-3 serine residues. It has been found that incorporation of metal ions into catalyticpockets increase the activity of the synzymes. The structures of the 17 most active catalysts selectedfrom the library of complexes obtained with Cu ion varied from 16 derivatives complexed withZn ion. For all of them, a very high reaction rate during the preliminary phase of measurementswas followed by a substantial slowdown after 1 h. The catalytic activity gradually diminished aftersubsequent re-use. HPLC analysis of amide bond splitting confirmed that substrate consumptionproceeded in two stages. In the preliminary stage 24⁻40% of the substrate was rapidly hydrolysedfollowed by the substantially lower reaction rate. Nevertheless, using the most competentsynzymes product of hydrolysis was formed with a yield of 60⁻83% after 48h under mild andstrictly biomimetic conditions.
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http://dx.doi.org/10.3390/ma12040578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6416662PMC
February 2019

Butanol Synthesis Routes for Biofuel Production: Trends and Perspectives.

Materials (Basel) 2019 Jan 23;12(3). Epub 2019 Jan 23.

Institute of Fermentation Technology and Microbiology, Faculty of Biochemistry and Food Sciences, Lodz University of Technology, Wolczanska 171/173, 90-924 Lodz, Poland.

Butanol has similar characteristics to gasoline, and could provide an alternative oxygenate to ethanol in blended fuels. Butanol can be produced either via the biotechnological route, using microorganisms such as clostridia, or by the chemical route, using petroleum. Recently, interest has grown in the possibility of catalytic coupling of bioethanol into butanol over various heterogenic systems. This reaction has great potential, and could be a step towards overcoming the disadvantages of bioethanol as a sustainable transportation fuel. This paper summarizes the latest research on butanol synthesis for the production of biofuels in different biotechnological and chemical ways; it also compares potentialities and limitations of these strategies.
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http://dx.doi.org/10.3390/ma12030350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6384976PMC
January 2019

The cellular effects of novel triazine nitrogen mustards in glioblastoma LBC3, LN-18 and LN-229 cell lines.

Invest New Drugs 2019 10 15;37(5):984-993. Epub 2019 Jan 15.

Department of Pharmaceutical Biochemistry, Medical University of Bialystok, Bialystok, Poland.

1,3,5-triazine is an important heterocyclic skeleton for mono, two or three 2-chloroethylamine groups. The study presented here provides novel information on cellular effects of 1,3,5-triazine with mono, two or three 2-chloroethylamine groups in glioblastoma LBC3, LN-18 and LN-229 cell lines. In our study, the most cytotoxic effect was observed in 1,3,5-triazine with three 2-chloroethylamine groups (12f compound). It has been demonstrated that 12f induce time- and dose-dependent cytotoxicity in all investigated glioma cell lines. Apart from that in glioblastoma cells, treated with 12f compound, we noticed strong induction of apoptosis. In conclusion, this research provides novel information concerning cellular effects of apoptosis in LBC3, LN-18 and LN-229 cell lines. Moreover, we suggest that 12f compound may be a candidate for further evaluation as an effective chemotherapeutic agent for human glioblastoma cells.
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http://dx.doi.org/10.1007/s10637-018-0712-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6736897PMC
October 2019

Study on the Materials Formed by Self-Assembling Hydrophobic, Aromatic Peptides Dedicated to Be Used for Regenerative Medicine.

Chem Biodivers 2019 Mar 26;16(3):e1800543. Epub 2019 Feb 26.

Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland.

The aims of this study were to identify the short aromatic peptides which are able to form highly ordered amyloid-like structures in self-assembling processes, to test the influence of length of hydrophobic peptides on tendency to aggregation, and to check if aggregated peptides fulfill requirements expected for materials useful for scaffolding. All tested hydrophobic peptides were prepared on solid phase by using DMT/NMM/TsO as a coupling reagent. The progress of aggregation was studied by set of independent tests. All aggregated peptides were found stable under in vitro conditions. All fibrous material formed by self-assembling of peptides does not show any cytotoxic effects on L929 fibroblast cells. Peptides containing tyrosine and tryptophan residues even effectively accelerated the proliferation and stimulated the activity of L929 fibroblasts.
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http://dx.doi.org/10.1002/cbdv.201800543DOI Listing
March 2019

Orthogonal Functionalization of Nanodiamond Particles after Laser Modification and Treatment with Aromatic Amine Derivatives.

Nanomaterials (Basel) 2018 Nov 5;8(11). Epub 2018 Nov 5.

Institute of Materials Science and Engineering, Lodz University of Technology, Stefanowskiego 1/15, 90-924 Lodz, Poland.

A laser system with a wavelength of 1064 nm was used to generate sp² carbon on the surfaces of nanodiamond particles (NDPs). The modified by microplasma NDPs were analysed using FT-IR and Raman spectroscopy. Raman spectra confirmed that graphitization had occurred on the surfaces of the NDPs. The extent of graphitization depended on the average power used in the laser treatment process. FT-IR analysis revealed that the presence of C=C bonds in all spectra of the laser-modified powder. The characteristic peaks for olefinic bonds were much more intense than in the case of untreated powder and grew in intensity as the average laser power increased. The olefinized nanodiamond powder was further functionalized using aromatic amines via in situ generated diazonium salts. It was also found that isokinetic mixtures of structurally diverse aromatic amines containing different functional groups (acid, amine) could be used to functionalize the surfaces of the laser-modified nanoparticles leading to an amphiphilic carbon nanomaterial. This enables one-step orthogonal functionalization and opens the possibility of selectively incorporating molecules with diverse biological activities on the surfaces of NDPs. Modified NDPs with amphiphilic properties resulting from the presence carboxyl and amine groups were used to incorporate simultaneously folic acid (FA-CONH-(CH₂)₅-COOH) and 5(6)-carboxyfluorescein (FL-CONH-(CH₂)₂-NH₂) derivatives on the surface of material under biocompatible procedures.
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http://dx.doi.org/10.3390/nano8110908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6266277PMC
November 2018

Towards Intelligent Drug Design System: Application of Artificial Dipeptide Receptor Library in QSAR-Oriented Studies.

Molecules 2018 Aug 6;23(8). Epub 2018 Aug 6.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Comenius University, Odbojarov 10, 83232 Bratislava, Slovakia.

The pharmacophore properties of a new series of potential purinoreceptor (P2X) inhibitors determined using a coupled neural network and the partial least squares method with iterative variable elimination (IVE-PLS) are presented in a ligand-based comparative study of the molecular surface by comparative molecular surface analysis (CoMSA). Moreover, we focused on the interpretation of noticeable variations in the potential selectiveness of interactions of individual inhibitor-receptors due to their physicochemical properties; therefore, the library of artificial dipeptide receptors (ADP) was designed and examined. The resulting library response to individual inhibitors was arranged in the array, preprocessed and transformed by the principal component analysis (PCA) and PLS procedures. A dominant absolute contribution to PC1 of the Glu attached to heptanoic gating acid and Phe bonded to the linker -phenylenediamine/triazine scaffold was revealed by the PCA. The IVE-PLS procedure indicated the receptor systems with predominant Pro bonded to the linker and Glu, Gln, Cys and Val directly attached to the gating acid. The proposed comprehensive ligand-based and simplified structure-based methodology allows the in-depth study of the performance of peptide receptors against the tested set of compounds.
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http://dx.doi.org/10.3390/molecules23081964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222794PMC
August 2018

Novel tool in rheumatoid arthritis diagnosis-The usage of urease flap region peptidomimetics.

J Pept Sci 2018 Jun;24(6):e3084

Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924, Lodz, Poland.

Rheumatoid arthritis (RA) is an autoimmune inflammatory disease. Early diagnosis can prevent joint erosion. However, available biomarkers do not always allow for clear distinction between RA and non-RA individuals. It has become known that bacteria/viruses are among the environmental triggers that initiate RA via multiple molecular mechanisms. Thus, to better understand the role of bacteria in RA, we synthetized 6 peptidomimetics of bacterial ureases' flap region. These peptides were then used to distinguish RA patients from healthy people sera by immunoblotting. Most patients' sera were bound to peptidomimetic characteristic for Enterobacter sp. and Klebsiella sp. flap urease. We also found similarities between peptidomimetic sequence and human proteins connected with RA. This pilot study suggests that bacteria may trigger RA via mechanism of molecular mimicry of urease to host proteins and ureases flap peptidomimetics may be potential candidate as a new additional diagnostic test.
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http://dx.doi.org/10.1002/psc.3084DOI Listing
June 2018

Search for Fibrous Aggregates Potentially Useful in Regenerative Medicine Formed under Physiological Conditions by Self-Assembling Short Peptides Containing Two Identical Aromatic Amino Acid Residues.

Molecules 2018 Mar 2;23(3). Epub 2018 Mar 2.

Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

This study investigates the propensity of short peptides to self-organize and the influence of aggregates on cell cultures. The dipeptides were derived from both enantiomers of identical aromatic amino acids and tripeptides were prepared from two identical aromatic amino acids with one cysteine or methionine residue in the C-terminal, N-terminal, or central position. The formation or absence of fibrous structures under physiological conditions was established using Congo Red and Thioflavine T assays as well as by microscopic examination using normal and polarized light. The in vitro stability of the aggregates in buffered saline solution was assessed over 30 days. Materials with potential for use in regenerative medicine were selected based on the cytotoxicity of the peptides to the endothelial cell line EA.hy 926 and the wettability of the surfaces of the films, as well as using scanning electron microscopy. The criteria were fulfilled by H-PhePhe-OH, H-CysPhePhe-OH, H-CysTyrTyr-OH, H-PhePheCys-OH, H-TyrTyrMet-OH, and H-TyrMetTyr-OH. Our preliminary results suggest that the morphology and cell viability of L919 fibroblast cells do not depend on the stereochemistry of the self-organizing peptides.
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http://dx.doi.org/10.3390/molecules23030568DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6017032PMC
March 2018

New methodology for automated SPOT synthesis of peptides on cellulose using 1,3,5-triazine derivatives as linkers and as coupling reagents.

J Pept Sci 2018 Feb;24(2)

Institute of Organic Chemistry, Lodz University of Technology, 90-924, Lodz, Poland.

Two new rigid bi-aromatic linkers for synthesis of peptide arrays by SPOT methodology were obtained from cellulose treated with 2,4-dichloro-6-methoxy-1,3,5-triazine. Reaction with m-phenylenediamine gave non-cleavable TYPE I linker which enabled attachment of the peptides via resistant to harsh reaction conditions amide, ether, and amine bonds. Reaction with 3-Fmoc-aminobenzoic acid followed by thermal isomerization of the intermediate "superactive" ester producing an amide-like bond gave TYPE II linker that was very stable during peptide synthesis. However, the peptide was cleavable, with fragment of the linker, in the presence of 1 M LiOH solution. The uniform loading of the cellulose and efficient synthesis of the peptide array was achieved by using N-(4,6-dimethoxy-1,3,5-triazin-1-yl)-N-methylmorpholinium 4-toluenesulfonate as the coupling reagent.
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http://dx.doi.org/10.1002/psc.3063DOI Listing
February 2018

Carbon nanotubes functionalized with folic acid attached via biomimetic peptide linker.

Nanomedicine (Lond) 2017 Sep 17;12(18):2161-2182. Epub 2017 Aug 17.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90924 Lodz, Poland.

Aim: Anchoring folic acid (FA) with a biomimetic peptidic linker resistant to proteolytic degradation to act as a homing device on functionalized carbon nanotubes.

Materials & Methods: Ethylenediamine was attached to oxidized multiwalled carbon nanotubes (MWNTs) using 4-(4,6-dimethoxy-[1,3,5]triazin-2-yl)-4-methylmorpholinium tetrafluoroborate. FA was coupled with 6-aminohexanoic acid and derivatives of β-alanine, affording four intermediates, which connected to the MWNTs via peptidic linkers of various lengths.

Results: Biomimetic nanomaterials were produced with FA as a homing molecule. The structure and properties of the nanomaterials were analyzed, confirming the versatility of the peptides used as linkers.

Conclusion: Conjugates of FA attached to MWNTs via peptide linkers prepared from β-alanine residues are resistant to proteolytic degradation. Viability in colon cancer cells and normal colonocytes confirmed their lack of cytotoxicity.
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http://dx.doi.org/10.2217/nnm-2017-0120DOI Listing
September 2017

The quest for the shortest fragments of A (13-19) and B (12-17) responsible for the aggregation of human insulin.

Nanomedicine (Lond) 2016 08 27;11(16):2083-101. Epub 2016 Jul 27.

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

Aim: To identify the shortest components of A13-A19, B12-B17 fragments capable for fibrillation and to validate the dependability of aggregation on the presence of hydroxyl group engaged in the 'tyrosine kissing'.

Materials & Methods: Fragments A13-A19 and B12-B17 of insulin and all shortened analogues were obtained by using DMT/NMM/TosO(-) as a coupling reagent. The aggregation was studied by three independent tests.

Results: Studies on the susceptibility to aggregation of truncated analogs of insulin amyloidogenic core show three groups of peptides.

Conclusion: Truncation of A13-A419 fragment shows that fibrous structures are formed by all peptides bearing (13)H-LeuTyr-OH(14). Propensity to aggregation was found for (16)H-TyrLeu-OH(17) B12-B17 fragment. Tyrosine residue modification by incorporation of tert-butyl group on hydroxyl function gave analogues still predisposed to aggregation.
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http://dx.doi.org/10.2217/nnm-2016-0100DOI Listing
August 2016

Synthesis of Arylamino-1,3,5-triazines Functionalized with Alkylatin 2-chloroethylamine Fragments and Studies of their Cytotoxicity on the Breast Cancer MCF-7 Cell Line.

Anticancer Agents Med Chem 2016 ;16(11):1435-1444

Institute of Organic Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland.

Dual action alkyl(aryl)amino-1,3,5-triazines functionalized with nitrogen mustards were obtained by treating 2-alkyl(aryl) amino-4-chloro-6-methoxy-1,3,5-triazines with amines or amino acid methyl esters, followed by reactions with 1,4-diazabicyclo[2.2.2]octane (DABCO) and rearrangement with an opening diazabicyclic fragment, leading to the formation of 2-chloroethylamino moiety. In vitro antitumor activity was tested in the standard human breast cancer MCF-7 and MDA-MB-231cell lines using flow cytometry, based on the detection of apoptosis through qualitative analysis of morphological changes, DNA fragmentation, DNA loss and membrane changes. For all the compounds studied, induced apoptosis was substantially stronger than necrosis at concentrations of both 5 μM and 50 μM, and in some cases there was no increase in necrotic cell death for the estrogen dependent MCF-7 cell line. The most active compounds were derivatives of triazine substituted with phenylamine (IC50 = 12.30 μM) and/or p-tolylamine fragments (IC50 = 7.40 μM).
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http://dx.doi.org/10.2174/1871520616666160204111430DOI Listing
June 2017

Cellulose Template Assembled Synthetic Peptides as Molecular Receptors.

Curr Protein Pept Sci 2016 ;17(2):117-26

Institute of Organic Chemistry, Faculty of Chemistry, Lodz University of Technology, P.O. Box: 0000- 000, 90-924 Lodz, Poland.

The relatively simple peptides assembled on the templates are excellent mimic of complex conformational and functional defined binding sites of proteins. The main benefit of experiments with artificial receptors arises from the relative simplicity of the interacting host-guest system allowing the understanding of the rules controlling the model process of the molecular recognition. Efficient modification of molecular receptors by using rational design of their structure or combinatorial methods is crucial for verification of any hypothesis concerning the binding forces or enhancing the binding properties. This approach is presenting promising strategy for understanding mode of action and the control of biological functions of proteins, for designing new pharmaceutically active compounds, new tools for medical diagnostic and molecular sensing.
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http://dx.doi.org/10.2174/138920371702160209122710DOI Listing
October 2016

Preliminary studies on application of library of artificial receptors for differentiation of metabolites in urine of healthy and cancer bearing mice.

Acta Pol Pharm 2014 Nov-Dec;71(6):941-53

A library of artificial receptors formed by the self-organization of N-lipidated peptides attached to the cellulose via m-aminophenylamino-1,3,5-triazine was used for differentiation of metabolites in urine of healthy and cancer bearing mice. The interactions of urine metabolites with the receptors were visualized by using competitive adsorption-desorption of an appropriate reporter dye. Analysis of the binding pattern (fingerprint) of urine metabolites from healthy and from cancer suffering mice showed that there were several structures among 120-elements molecular receptors which were able to differentiate bonded ligands depending on the healthy state. For all three tested types of cancers two structures: Lipid-Pro-Ala-NH-C6H4-NH-DMT-cellulose and Lipid-Arg-Pro-NH-C6H4-NH-DMT-cellulose were selected as diagnostic.
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June 2015

Probing an artificial polypeptide receptor library using a series of novel histamine H3 receptor ligands.

Comb Chem High Throughput Screen 2014 Feb;17(2):141-56

Institute of Chemistry, University of Silesia, 40-006 Katowice, Poland.

An artificial polypeptide receptor (APR) library was created by using the self-organization of N-lipidated peptides attached to cellulose via m-aminophenylamino-1,3,5-triazine. The response of the library was probed using a series of novel H3 receptor ligands. Since no guidelines on how to design an APRs selective vs certain receptor types exist, a diverse set of amino acids (Ala, Trp, Pro, Glu, His, Lys and Ser) were used and coupled with one of three gating fatty acids (palmitic, ricinoleic or capric). A competitive adsorption-desorption of an appropriate reporter dye was used for the indirect visualization of the interactions of guests with particular receptors. The resulted library response to individual inhibitors was then arranged in a matrix, preprocessed and analyzed using the principal component analysis (PCA) and partial least squares (PLS) method. The most important conclusion obtained from the PCA analysis is that the library differentiates the probed compounds according to the lipophilicity of the gating unit. The PC3 with a dominant absolute contribution of the receptors containing Glu allowed for the best separation of the ligands with respect to their activity. This conclusion is in agreement with the fact that Glu 206 is a genuine ligand counterpart in the natural histamine receptor.
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http://dx.doi.org/10.2174/13862073113169990054DOI Listing
February 2014

N-lipidated oligopeptides immobilized on cellulose as new type of organocatalysts.

Comb Chem High Throughput Screen 2013 Jun;16(7):562-71

Institute of Organic Chemistry, Technical University of Lodz, Zeromskiego116, 90-924 Lodz, Poland.

A library of supramolecular structures formed by self-organization of N-lipidated tripeptides, dipeptides and N-acylated amino acids attached to cellulose according to the TASP concept via aminophenylamino-1,3,5-triazine was synthesized and the catalytic activity of the structures was studied. Intensive catalytic activity in solvolysis of sterically hindered Z-Aib-Aib-ONp under ambient conditions was observed for structures bearing the catalytic triad as well as for structures with the peptide fragment shortened to a dipeptide or even a single Ser, Glu or His residue, but not for structures bearing alanine or phenylalanine residues. For all structures with a dipeptide or a single amino acid residue and for most of tripeptide structures the progress of solvolysis was stopped after the concentration of the nitrophenolate ion reached 0.5-0.7 x 10-4 M/L. Only in the case of catalysts with glutamic acid residues in the tripeptide fragment, solvolysis proceeded until all the substrate was consumed.
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http://dx.doi.org/10.2174/1386207311316070006DOI Listing
June 2013

Bacterial urease and its role in long-lasting human diseases.

Curr Protein Pept Sci 2012 Dec;13(8):789-806

Department of Microbiology, Institute of Biology, The Jan Kochanowski University, ul. Swietokrzyska 15, 25-406 Kielce, Poland.

Urease is a virulence factor found in various pathogenic bacteria. It is essential in colonization of a host organism and in maintenance of bacterial cells in tissues. Due to its enzymatic activity, urease has a toxic effect on human cells. The presence of ureolytic activity is an important marker of a number of bacterial infections. Urease is also an immunogenic protein and is recognized by antibodies present in human sera. The presence of such antibodies is connected with progress of several long-lasting diseases, like rheumatoid arthritis, atherosclerosis or urinary tract infections. In bacterial ureases, motives with a sequence and/or structure similar to human proteins may occur. This phenomenon, known as molecular mimicry, leads to the appearance of autoantibodies, which take part in host molecules destruction. Detection of antibodies- binding motives (epitopes) in bacterial proteins is a complex process. However, organic chemistry tools, such as synthetic peptide libraries, are helpful in both, epitope mapping as well as in serologic investigations. In this review, we present a synthetic report on a molecular organization of bacterial ureases - genetic as well as structural. We characterize methods used in detecting urease and ureolytic activity, including techniques applied in disease diagnostic processes and in chemical synthesis of urease epitopes. The review also provides a summary of knowledge about a toxic effect of bacterial ureases on human body and about occurrence of anti-urease antibodies in long-lasting diseases.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3816311PMC
http://dx.doi.org/10.2174/138920312804871094DOI Listing
December 2012

Structure-activity relationship in binding ligands to library of artificial receptors: the search for biocompatible sensor.

Bioelectrochemistry 2010 Nov 12;80(1):2-9. Epub 2010 Jun 12.

Institute of Organic Chemistry, Technical University of Łódź, 90-924 Łódź, Poland.

Structure-activity relationship (SAR) analysis was applied for studies of docking of colored ligands to library of artificial receptors formed by self-assembly of N-lipidated amino acids immobilised on the cellulose support. The studies show that the binding depends mainly on the structure of amino acid fragment but influence of N-lipidic fragment is less important.
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http://dx.doi.org/10.1016/j.bioelechem.2010.06.001DOI Listing
November 2010

Application of a library of artificial receptors formed by the self-organization of N-lipidated peptides immobilized on cellulose in studying the effects of the incorporation of a fluorine atom.

J Comb Chem 2009 May-Jun;11(3):446-51

Institute of Organic Chemistry, Technical University of Łodz, Łodz, Poland.

A library of artificial receptors formed by the self-organization of N-lipidated peptides attached to cellulose via m-aminophenylamino-1,3,5-triazine was used for docking pairs of small colorless N-phenylpiperazines with and without a fluorine atom in the phenyl ring. The interactions of guests with the receptors were visualized by using competitive adsorption-desorption of an appropriate reporter dye. Several library members demonstrated attributes characteristic of the detection of alterations in the guest structure caused by the substitution of one hydrogen atom with fluorine. Analysis of the binding pattern of N-phenylpiperazine derivatives showed two characteristic bonding patterns: one with stronger binding of fluorinated analogues and weaker binding of native phenyl substituted analogues by the most of the receptors studied and another one with stronger binding of native hydrogen substituted compounds and respectively weaker binding of fluorinated analogues of guest molecules by receptors with tryptophan inside the binding pocket.
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http://dx.doi.org/10.1021/cc800213zDOI Listing
July 2009
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