scholarly journals Novel Pathway for Efficient Covalent Modification of Polyester Materials of Different Design to Prepare Biomimetic Surfaces

Polymers ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 1299 ◽  
Author(s):  
Viktor Korzhikov-Vlakh ◽  
Ilia Averianov ◽  
Ekaterina Sinitsyna ◽  
Yuliya Nashchekina ◽  
Dmitry Polyakov ◽  
...  
Keyword(s):  
Covalent Binding ◽  
Polymer Surface ◽  
Material Design ◽  
Covalent Modification ◽  
Covalent Attachment ◽  
Poly Lactic Acid ◽  
Elevated Concentration ◽  
The Novel ◽  
Biomimetic Surfaces ◽  
Reactive Groups

To form modern materials with biomimic surfaces, the novel pathway for surface functionalization with specific ligands of well-known and widely used polyester-based rigid media was developed and optimized. Two types of material bases, namely, poly(lactic acid) and poly(ε-caprolactone), as well as two types of material design, e.g., supermacroporous matrices and nanoparticles (NPs), were modified via covalent attachment of preliminary oxidized polyvinylsaccharide poly(2-deoxy-N-methacryloylamido-d-glucose) (PMAG). This polymer, being highly biocompatible and bioinspired, was used to enhance hydrophilicity of the polymer surface and to provide the elevated concentration of reactive groups required for covalent binding of bioligands of choice. The specialties of the interaction of PMAG and its preliminary formed bioconjugates with a chemically activated polyester surface were studied and thoroughly discussed. The supermacroporous materials modified with cell adhesion motifs and Arg-Gly-Asp-containing peptide (RGD-peptide) were tested in the experiments on bone tissue engineering. In turn, the NPs were modified with bioligands (“self-peptide” or camel antibodies) to control their phagocytosis that can be important, for example, for the preparation of drug delivery systems.

scholarly journals Radiation-Induced Graft Immobilization (RIGI): Covalent Binding of Non-Vinyl Compounds on Polymer Membranes

Polymers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1849
Author(s):  
Martin Schmidt ◽  
Stefan Zahn ◽  
Florian Gehlhaar ◽  
Andrea Prager ◽  
Jan Griebel ◽  
...  
Keyword(s):  
Photoelectron Spectroscopy ◽  
Polyvinylidene Fluoride ◽  
Covalent Binding ◽  
Polymer Surface ◽  
Experimental Studies ◽  
Polymeric Materials ◽  
Covalent Attachment ◽  
Minor Role ◽  
Water Radiolysis ◽  
Radiation Induced

Radiation-induced graft immobilization (RIGI) is a novel method for the covalent binding of substances on polymeric materials without the use of additional chemicals. In contrast to the well-known radiation-induced graft polymerization (RIGP), RIGI can use non-vinyl compounds such as small and large functional molecules, hydrophilic polymers, or even enzymes. In a one-step electron-beam-based process, immobilization can be performed in a clean, fast, and continuous operation mode, as required for industrial applications. This study proposes a reaction mechanism using polyvinylidene fluoride (PVDF) and two small model molecules, glycine and taurine, in aqueous solution. Covalent coupling of single molecules is achieved by radical recombination and alkene addition reactions, with water radiolysis playing a crucial role in the formation of reactive solute species. Hydroxyl radicals contribute mainly to the immobilization, while solvated electrons and hydrogen radicals play a minor role. Release of fluoride is mainly induced by direct ionization of the polymer and supported by water. Hydrophobic chains attached to cations appear to enhance the covalent attachment of solutes to the polymer surface. Computational work is complemented by experimental studies, including X-ray photoelectron spectroscopy (XPS) and fluoride high-performance ion chromatography (HPIC).

scholarly journals Non-Covalent Binding of Tripeptides-Containing Tryptophan to Polynucleotides and Photochemical Deamination of Modified Tyrosine to Quinone Methide Leading to Covalent Attachment

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4315
Author(s):  
Antonija Erben ◽  
Igor Sviben ◽  
Branka Mihaljević ◽  
Ivo Piantanida ◽  
Nikola Basarić
Keyword(s):  
Quantum Yield ◽  
Photophysical Properties ◽  
Covalent Binding ◽  
Quinone Methide ◽  
Covalent Attachment ◽  
Dna And Rna ◽  
Pair Composition ◽  
Aqueous Solvent ◽  
Fluorometric Study ◽  
Spectral Responses

A series of tripeptides TrpTrpPhe (1), TrpTrpTyr (2), and TrpTrpTyr[CH2N(CH3)2] (3) were synthesized, and their photophysical properties and non-covalent binding to polynucleotides were investigated. Fluorescent Trp residues (quantum yield in aqueous solvent ΦF = 0.03–0.06), allowed for the fluorometric study of non-covalent binding to DNA and RNA. Moreover, high and similar affinities of 2×HCl and 3×HCl to all studied double stranded (ds)-polynucleotides were found (logKa = 6.0–6.8). However, the fluorescence spectral responses were strongly dependent on base pair composition: the GC-containing polynucleotides efficiently quenched Trp emission, at variance to AT- or AU-polynucleotides, which induced bisignate response. Namely, addition of AT(U) polynucleotides at excess over studied peptide induced the quenching (attributed to aggregation in the grooves of polynucleotides), whereas at excess of DNA/RNA over peptide the fluorescence increase of Trp was observed. The thermal denaturation and circular dichroism (CD) experiments supported peptides binding within the grooves of polynucleotides. The photogenerated quinone methide (QM) reacts with nucleophiles giving adducts, as demonstrated by the photomethanolysis (quantum yield ΦR = 0.11–0.13). Furthermore, we have demonstrated photoalkylation of AT oligonucleotides by QM, at variance to previous reports describing the highest reactivity of QMs with the GC reach regions of polynucleotides. Our investigations show a proof of principle that QM precursor can be imbedded into a peptide and used as a photochemical switch to enable alkylation of polynucleotides, enabling further applications in chemistry and biology.

scholarly journals Mechanism of Covalent Binding of Ibrutinib to Bruton’s Tyrosine Kinase revealed by QM/MM Calculations

2020 ◽  
Author(s):  
Angus Voice ◽  
Gary Tresadern ◽  
Rebecca Twidale ◽  
Herman Van Vlijmen ◽  
Adrian Mulholland
Keyword(s):  
Tyrosine Kinase ◽  
Covalent Binding ◽  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Modification ◽  
Mechanistic Study ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Covalent Inhibitors ◽  
Covalent Bond Formation

<p>Ibrutinib is the first covalent inhibitor of Bruton’s tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition is crucial for the design of safer and more selective covalent inhibitors that target BTK. There are questions surrounding the precise mechanism of covalent bond formation in BTK as there is no appropriate active site residue that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. To address this, we have investigated several mechanistic pathways of covalent modification of C481 in BTK by ibrutinib using QM/MM reaction simulations. The lowest energy pathway we identified involves a direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (DG<sup>‡</sup>=10.5 kcal mol<sup>-1</sup>) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and related proteins. </p>

scholarly journals Mannitol-1-phosphate dehydrogenase of Escherichia coli Chemical properties and binding of substrates

1986 ◽  
Vol 239 (2) ◽  
pp. 435-443 ◽  
Author(s):  
T Chase
Keyword(s):  
Amino Acid ◽  
Amino Acid Analysis ◽  
Dissociation Constants ◽  
Ph Dependence ◽  
Covalent Binding ◽  
Polyacrylamide Gel Electrophoresis ◽  
Thiol Group ◽  
Covalent Modification ◽  
Protective Effects ◽  
Phosphate Complex

Mannitol-1-phosphate dehydrogenase was purified to homogeneity, and some chemical and physical properties were examined. The isoelectric point is 4.19. Amino acid analysis and polyacrylamide-gel electrophoresis in presence of SDS indicate a subunit Mr of about 22,000, whereas gel filtration and electrophoresis of the native enzyme indicate an Mr of 45,000. Thus the enzyme is a dimer. Amino acid analysis showed cysteine, tyrosine, histidine and tryptophan to be present in low quantities, one, three, four and four residues per subunit respectively. The zinc content is not significant to activity. The enzyme is inactivated (greater than 99%) by reaction of 5,5′-dithiobis-(2-nitrobenzoate) with the single thiol group; the inactivation rate depends hyperbolically on reagent concentration, indicating non-covalent binding of the reagent before covalent modification. The pH-dependence indicated a pKa greater than 10.5 for the thiol group. Coenzymes (NAD+ and NADH) at saturating concentrations protect completely against reaction with 5,5′-dithiobis-(2-nitrobenzoate), and substrates (mannitol 1-phosphate, fructose 6-phosphate) protect strongly but not completely. These results suggest that the thiol group is near the catalytic site, and indicate that substrates as well as coenzymes bind to free enzyme. Dissociation constants were determined from these protective effects: 0.6 +/- 0.1 microM for NADH, 0.2 +/- 0.03 mM for NAD+, 9 +/- 3 microM for mannitol 1-phosphate, 0.06 +/- 0.03 mM for fructose 6-phosphate. The binding order for reaction thus may be random for mannitol 1-phosphate oxidation, though ordered for fructose 6-phosphate reduction. Coenzyme and substrate binding in the E X NADH-mannitol 1-phosphate complex is weaker than in the binary complexes, though in the E X NADH+-fructose 6-phosphate complex binding is stronger.

Covalent immobilization of enzyme on aminated woven poly (lactic acid) via ammonia plasma: evaluation of the optimum immobilization conditions

2016 ◽  
Vol 87 (10) ◽  
pp. 1177-1191 ◽  
Author(s):  
Ji Eun Song ◽  
Wha Soon Song ◽  
Sang Young Yeo ◽  
Hye Rim Kim ◽  
So Hee Lee
Keyword(s):  
Lactic Acid ◽  
Photoelectron Spectroscopy ◽  
Specific Activity ◽  
Covalent Binding ◽  
Covalent Immobilization ◽  
Poly Lactic Acid ◽  
Porcine Pancreas ◽  
Thermal Stabilities ◽  
Treatment Conditions ◽  
Immobilized Trypsin

The present study aims to develop an immobilization support from woven poly (lactic acid) (PLA) and establish the optimum immobilization conditions for trypsin. Woven PLA was modified by ammonia-based plasma treatment in order to incorporate amine groups on its surface. X-ray photoelectron spectroscopy analysis showed that the N1s composition of PLA increased significantly, from 0.66% to 5.92%, after ammonia-based plasma processing. Trypsin from porcine pancreas was immobilized onto modified woven PLA by covalent binding after activating PLA with glutaraldehyde (GA). The results indicated that the optimal GA treatment conditions were as follows: pH of 10.0, 2% GA (v/v), and 180 min crosslinking time. In addition, the optimum immobilization conditions were as follows: pH of 8.5, 10% (owf) of trypsin concentration, 30 min, and 25℃. Under the optimum conditions, the amount of immobilized enzyme on woven PLA was 0.28 mg/mg and specific activity was 3.763 U/mg. In addition, the pH and thermal stabilities of the immobilized trypsin were improved. The immobilized trypsin retained approximately 55% of its initial activity after 20 days of storage and exhibited the potential for repetitive use through approximately 15 cycles. GA crosslinking and trypsin immobilization were found to improve the roughness of the PLA surface and increase its hydrophobicity. The data indicate that modified woven PLA, used as an immobilization support, shows suitable properties for use as a biocatalytic material in enzymatic applications.

scholarly journals Characterisation of Zampanolide as a Microtubule-Stabilizing Agent

2021 ◽  
Author(s):  
◽  
Jessica J. Field
Keyword(s):  
Binding Site ◽  
Cell Lines ◽  
Efflux Pump ◽  
Covalent Binding ◽  
Covalent Modification ◽  
Cancer Drug ◽  
Side Chain ◽  
Drug Efflux ◽  
New Generation

<p>Microtubule-stabilizing agents (MSAs) are extremely important chemotherapeutic drugs since microtubules (MTs) are one of the most successful cancer drug targets. Currently there are four MSAs that are clinically used for the treatment of cancer. Cancer cells, however, can develop resistance towards these drugs, the most common being over-expression of the P-glycoprotein drug efflux pump. Zampanolide (ZMP), a novel secondary metabolite isolated from a marine sponge consists of a 20-membered macrolide ring with an unusual N-acyl-hemiaminal side chain. It is a potent MSA with similar cellular effects to the clinically relevant MSAs, Taxol®, Taxotere® and Ixempra®. ZMP has a small number of stereogenic centers and therefore is relatively easier to synthesize than other macrolide natural products. Using established cancer cell lines and isolated bovine brain tubulin ZMP in the present study was further characterized as a potential anti-cancer compound and was shown to have significant advantages over currently used MSAs. These studies provided insight into how this important drug class induces MT assembly, suggesting strategies for the development of new generation MSAs for use in the clinic. ZMP and its less active analog dactylolide competed with paclitaxel for binding to MTs and represented a novel MSA chemotype. Unlike traditional taxoid site ligands, ZMP remained significantly more cytotoxic in cell lines with mutations in the taxoid binding site, and behaved in an unusual manner in vitro. This was later found to be due to its mechanism of binding which involved covalent modification of two amino acids in the taxoid binding site, histidine 229 as the major product and asparagine 228 as the minor product. Alkylation of both these luminal site residues was also detected in unassembled tubulin, providing the first direct evidence that the taxoid binding site exists in unassembled tubulin and suggesting that the induction of MT nucleation by MSAs may proceed through an allosteric mechanism. X-ray crystallography data confirmed the presence of this binding site in unassembled tubulin and indicated that covalent modification occurs at C9 of ZMP with the NE2 of the histidine side chain. The potent stabilization of MTs observed with ZMP occurred due to its side chain interaction with the stabilizing M-loop of β-tubulin. In unassembled tubulin the M-loop is unordered. Upon ZMP binding, it is restructured into a short, well-defined helix. It is this restructuring that leads to the potent stabilization by ZMP and most likely other MSAs, including those currently used in the clinic. This information provides a basis for structure-guided drug engineering to design and develop new generation MSAs with potent stabilizing activity. In addition, covalent binding of ZMP means that it is able to avoid drug efflux pumps and thus evade the main mechanism of resistance presented to MSAs in the clinic. It was shown by studying structure-activity relationships that there are a number of key chemical motifs in ZMP responsible for its potent activity. Simpler analog structures that retain significant stabilizing activity could be used as lead compounds for further drug development. Moreover, MSAs have clinically relevant anti-angiogenic and vascular-disrupting properties, and ZMP was also shown to potently inhibit cell migration and thus have possible benefits as a vasculature-targeting compound. It was concluded that ZMP is a potent covalently-binding MSA in both cells and in vitro. Given these promising results, further preclinical development of the compound is warranted.</p>

scholarly journals Mechanism of Covalent Binding of Ibrutinib to Bruton’s Tyrosine Kinase revealed by QM/MM Calculations

2020 ◽  
Author(s):  
Angus Voice ◽  
Gary Tresadern ◽  
Rebecca Twidale ◽  
Herman Van Vlijmen ◽  
Adrian Mulholland
Keyword(s):  
Tyrosine Kinase ◽  
Covalent Binding ◽  
Bond Formation ◽  
Covalent Bond ◽  
Covalent Modification ◽  
Mechanistic Study ◽  
Bruton’S Tyrosine Kinase ◽  
Bruton's Tyrosine Kinase ◽  
Covalent Inhibitors ◽  
Covalent Bond Formation

<p>Ibrutinib is the first covalent inhibitor of Bruton’s tyrosine kinase (BTK) to be used in the treatment of B-cell cancers. Understanding the mechanism of covalent inhibition is crucial for the design of safer and more selective covalent inhibitors that target BTK. There are questions surrounding the precise mechanism of covalent bond formation in BTK as there is no appropriate active site residue that can act as a base to deprotonate the cysteine thiol prior to covalent bond formation. To address this, we have investigated several mechanistic pathways of covalent modification of C481 in BTK by ibrutinib using QM/MM reaction simulations. The lowest energy pathway we identified involves a direct proton transfer from C481 to the acrylamide warhead in ibrutinib, followed by covalent bond formation to form an enol intermediate. There is a subsequent rate-limiting keto-enol tautomerisation step (DG<sup>‡</sup>=10.5 kcal mol<sup>-1</sup>) to reach the inactivated BTK/ibrutinib complex. Our results represent the first mechanistic study of BTK inactivation by ibrutinib to consider multiple mechanistic pathways. These findings should aid in the design of covalent drugs that target BTK and related proteins. </p>

scholarly journals Development and Characterization of a Biodegradable PLA Food Packaging Hold Monoterpene–Cyclodextrin Complexes against Alternaria alternata

Polymers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1720 ◽  
Author(s):  
Velázquez-Contreras Friné ◽  
Acevedo-Parra Hector ◽  
Nuño-Donlucas Sergio Manuel ◽  
Núñez-Delicado Estrella ◽  
Gabaldón José Antonio
Keyword(s):  
Alternaria Alternata ◽  
Food Packaging ◽  
Polymer Surface ◽  
Thermal Characterization ◽  
Intermolecular Forces ◽  
Polymer Chains ◽  
Economic Losses ◽  
Poly Lactic Acid ◽  
Injection Process

The fungi of the genus Alternaria are among the main pathogens causing post-harvest diseases and significant economic losses. The consumption of Alternaria contaminated foods may be a major risk to human health, as many Alternaria species produce several toxic mycotoxins and secondary metabolites. To protect consumer health and extend the shelf life of food products, the development of new ways of packaging is of outmost importance. The aim of this work was to investigate the antifungal capacity of a biodegradable poly(lactic acid) (PLA) package filled with thymol or carvacrol complexed in β-cyclodextrins (β-CDs) by the solubility method. Once solid complexes were obtained by spray drying, varying proportions (0.0%, 1.5%, 2.5%, and 5.0 wt%) of β-CD–thymol or β-CD–carvacrol were mixed with PLA for packaging development by injection process. The formation of stable complexes between β-CDs and carvacrol or thymol molecules was assessed by Fourier-transform infrared spectroscopy (FTIR). Mechanical, structural, and thermal characterization of the developed packaging was also carried out. The polymer surface showed a decrease in the number of cuts and folds as the amount of encapsulation increased, thereby reducing the stiffness of the packaging. In addition, thermogravimetric analysis (TGA) revealed a slight decrease in the temperature of degradation of PLA package as the concentration of the complexes increased, with β-CD–carvacrol or β-CDs–thymol complexes acting as plasticisers that lowered the intermolecular forces of the polymer chains, thereby improving the breaking point. Packages containing 2.5% and 5% β-CD–carvacrol, or 5% β-CD–thymol showed Alternaria alternata inhibition after 10 days of incubation revealing their potential uses in agrofood industry.

scholarly journals Photoactivated covalent binding of [3H]bilirubin to human serum albumin

1979 ◽  
Vol 181 (3) ◽  
pp. 779-781 ◽  
Author(s):  
D W Hutchinson ◽  
D S Mutopo
Keyword(s):  
Aqueous Solution ◽  
Human Serum Albumin ◽  
Serum Albumin ◽  
Human Serum ◽  
Good Yield ◽  
Covalent Binding ◽  
Covalent Attachment ◽  
Step Procedure ◽  
One Step ◽  
Degradation Studies

A one-step procedure has been developed for the preparation of [3H]bilirubin IX-alpha in good yield from unlabelled bilirubin. Irradiation of an aqueous solution of [3H]bilirubin IX-alpha in the presence of human serum albumin results in the covalent attachment of the bilirubin to the protein. Preliminary degradation studies have been carried out to locate the site of attachment of the bilirubin to the albumin.

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