scholarly journals Metallated Anticancer Peptides: An Expanded Mechanism that Encompasses Physical and Chemical Bilayer Disruption

2021 ◽  
Author(s):  
Fatih Comert ◽  
Frank Heinrich ◽  
Ananda Chowdhury ◽  
Mason Schoeneck ◽  
Caitlin Darling ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Uv Spectroscopy ◽  
Biologically Active ◽  
New Paradigm ◽  
Chronic Infections ◽  
Host Defense Peptides ◽  
Anticancer Peptides ◽  
Acyl Chains ◽  
Physical And Chemical ◽  
Chemical Strategy

Abstract In the search for novel broad-spectrum therapeutics to fight chronic infections, inflammation, and cancer, host defense peptides (HDPs) have garnered increasing interest. Characterizing their biologically-active conformations and minimum motifs for function represents a requisite step to developing them into efficacious and safe therapeutics. Here, we demonstrate that metallating HDPs is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that the metallated peptides not only physically but also chemically damage lipid membranes. Our testing ground features piscidins 1 and 3 (P1/3), two amphipathic, histidine-rich, membrane-interacting, and cell-penetrating HDPs that are α-helical bound to membranes. To investigate their membrane location, permeabilization effects, and lipid-oxidation capability, we employ neutron reflectometry, impedance spectroscopy, neutron diffraction, and UV spectroscopy. While P1-apo is more potent than P3-apo, metallation boosts their cytotoxicities by up to two-and seven-fold, respectively. Remarkably, P3 is particularly effective at inserting its metallated motif in bilayers, causing water crevices in the hydrocarbon region and placing Cu 2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where metallating HDPs to expand their mechanistic reach could be explored to design more potent peptide-based anticancer therapeutics.

scholarly journals Copper-binding anticancer peptides from the piscidin family: an expanded mechanism that encompasses physical and chemical bilayer disruption

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Fatih Comert ◽  
Frank Heinrich ◽  
Ananda Chowdhury ◽  
Mason Schoeneck ◽  
Caitlin Darling ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Uv Spectroscopy ◽  
Biologically Active ◽  
Copper Binding ◽  
New Paradigm ◽  
Chronic Infections ◽  
Host Defense Peptides ◽  
Anticancer Peptides ◽  
Acyl Chains ◽  
Physical And Chemical

AbstractIn the search for novel broad-spectrum therapeutics to fight chronic infections, inflammation, and cancer, host defense peptides (HDPs) have garnered increasing interest. Characterizing their biologically-active conformations and minimum motifs for function represents a requisite step to developing them into efficacious and safe therapeutics. Here, we demonstrate that metallating HDPs with Cu2+ is an effective chemical strategy to improve their cytotoxicity on cancer cells. Mechanistically, we find that prepared as Cu2+-complexes, the peptides not only physically but also chemically damage lipid membranes. Our testing ground features piscidins 1 and 3 (P1/3), two amphipathic, histidine-rich, membrane-interacting, and cell-penetrating HDPs that are α-helical bound to membranes. To investigate their membrane location, permeabilization effects, and lipid-oxidation capability, we employ neutron reflectometry, impedance spectroscopy, neutron diffraction, and UV spectroscopy. While P1-apo is more potent than P3-apo, metallation boosts their cytotoxicities by up to two- and seven-fold, respectively. Remarkably, P3-Cu2+ is particularly effective at inserting in bilayers, causing water crevices in the hydrocarbon region and placing Cu2+ near the double bonds of the acyl chains, as needed to oxidize them. This study points at a new paradigm where complexing HDPs with Cu2+ to expand their mechanistic reach could be explored to design more potent peptide-based anticancer therapeutics.

Computational Design of Biologically Active Anticancer Peptides and Their Interactions with Heterogeneous POPC/POPS Lipid Membranes

2019 ◽  
Vol 60 (1) ◽  
pp. 332-341 ◽  
Author(s):  
Maninder Singh ◽  
Vikash Kumar ◽  
Kamakshi Sikka ◽  
Ravi Thakur ◽  
Munesh Kumar Harioudh ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Computational Design ◽  
Biologically Active ◽  
Anticancer Peptides

scholarly journals Interactions of Linear Analogues of Battacin with Negatively Charged Lipid Membranes

Membranes ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. 192
Author(s):  
Kinga Burdach ◽  
Dagmara Tymecka ◽  
Aneta Urban ◽  
Robert Lasek ◽  
Dariusz Bartosik ◽  
...  
Keyword(s):  
Lipid Membranes ◽  
Liquid Crystalline ◽  
Lipid Membrane ◽  
Attenuated Total Reflection ◽  
Gram Positive ◽  
Insertion Depth ◽  
Force Microscopy ◽  
Acyl Chains ◽  
Hydrophobic Portion ◽  
Membrane Fluidization

The increasing resistance of bacteria to available antibiotics has stimulated the search for new antimicrobial compounds with less specific mechanisms of action. These include the ability to disrupt the structure of the cell membrane, which in turn leads to its damage. In this context, amphiphilic lipopeptides belong to the class of the compounds which may fulfill this requirement. In this paper, we describe two linear analogues of battacin with modified acyl chains to tune the balance between the hydrophilic and hydrophobic portion of lipopeptides. We demonstrate that both compounds display antimicrobial activity with the lowest values of minimum inhibitory concentrations found for Gram-positive pathogens. Therefore, their mechanism of action was evaluated on a molecular level using model lipid films mimicking the membrane of Gram-positive bacteria. The surface pressure measurements revealed that both lipopeptides show ability to bind and incorporate into the lipid monolayers, resulting in decreased ordering of lipids and membrane fluidization. Atomic force microscopy (AFM) imaging demonstrated that the exposure of the model bilayers to lipopeptides leads to a transition from the ordered gel phase to disordered liquid crystalline phase. This observation was confirmed by attenuated total reflection Fourier-transform infrared spectroscopy (ATR-FTIR) results, which revealed that lipopeptide action causes a substantial increase in the average tilt angle of lipid acyl chains with respect to the surface normal to compensate for lipopeptide insertion into the membrane. Moreover, the peptide moieties in both molecules do not adopt any well-defined secondary structure upon binding with the lipid membrane. It was also observed that a small difference in the structure of a lipophilic chain, altering the balance between hydrophobic and hydrophilic portion of the molecules, results in different insertion depth of the active compounds.

scholarly journals 7-Bromo-[1,2,5]selenadiazolo[3,4-d]pyridazin-4(5H)-one

Molbank ◽  
10.3390/m1229 ◽  
2021 ◽  
Vol 2021 (2) ◽  
pp. M1229
Author(s):  
Timofey N. Chmovzh ◽  
Oleg A. Rakitin
Keyword(s):  
Mass Spectrometry ◽  
Heterocyclic System ◽  
High Resolution Mass Spectrometry ◽  
Uv Spectroscopy ◽  
Hydrolysis Product ◽  
Selenium Dioxide ◽  
Biologically Active ◽  
Photovoltaic Materials ◽  
Organic Photovoltaic Materials ◽  
Ir And Uv Spectroscopy

New heterocyclic systems containing 1,2,5-chalcogenadiazoles are of great interest for the creation of organic photovoltaic materials and biologically active compounds. In this communication, 3,6-dibromopyridazine-4,5-diamine was investigated in reaction with selenium dioxide in order to obtain 4,7-dibromo-[1,2,5]selenadiazolo[3,4-d]pyridazine. We found that 7-bromo-[1,2,5]selenadiazolo[3,4-d]pyridazin-4(5H)-one, the first representative of the new heterocyclic system, was isolated as a hydrolysis product of the corresponding 4,7-dibromoderivative. The structure of the newly synthesized compound was established by means of elemental analysis, high-resolution mass spectrometry, 1H, 13C NMR, IR and UV spectroscopy, and mass spectrometry.

scholarly journals Changes in biologically active substances of stone fruits under the influence of low temperatures

2021 ◽  
Vol 34 ◽  
pp. 06017
Author(s):  
Irina Sobol ◽  
Ludmila Rodionova ◽  
Ludmila Donchenko ◽  
Artem Stepovoy
Keyword(s):  
Low Temperatures ◽  
Beta Carotene ◽  
Biologically Active Substances ◽  
Biologically Active ◽  
Carotene Content ◽  
Plum Varieties ◽  
Physical And Chemical ◽  
Active Substances ◽  
Acid Reduction ◽  
Pectin Substances

Sufficient consumption of natural biologically active substances (BAS) – vitamins, dietary fiber, mineral compounds – reduces the risk of developing diseases associated with negative external factors. A large number of BAS are contained in the cherry plum fruits. Cherry plum is characterized by storage short term, during which quality changes are possible. Studies have been conducted on the low temperatures effect the change of BAS in cherry plum fruits. Studied objects were five cherry plum varieties grown in the Russian southern regions – Dinnaya, Zhemchuzhina, Obilnaya, Puteshestvennitsa, Neberdzhayskaya ranyaya. It was found that during storage, the physical and chemical parameters change slightly, the dry substances content decreases (within 1.3-3.2 %), sugars (5.5-7.0 %), the total acids content increases (2.8 3.3 %). The BAS content slight decrease during storage does not significantly affect the nutritional value of cherry plum fruits. The ascorbic acid reduction is 9.8-17.3 %, the anthocyanins content decreases on average from 16.9 to 19.7 %, the beta-carotene content decreases by 8.7-14.8 %, the reduction level of pectin substances is 15.75-22.2 %. Thus, the freezing method application allows to preserve valuable BAS in cherry plum fruits and use them in the future as a basis for the production of functional food products.

scholarly journals Acyltransferase-mediated selection of the length of the fatty acyl chain and of the acylation site governs activation of bacterial RTX toxins

2020 ◽  
Vol 295 (28) ◽  
pp. 9268-9280 ◽  
Author(s):  
Adriana Osickova ◽  
Humaira Khaliq ◽  
Jiri Masin ◽  
David Jurnecka ◽  
Anna Sukova ◽  
...  
Keyword(s):  
Acyl Chain ◽  
Fatty Acyl ◽  
Biologically Active ◽  
Fatty Acyl Chain ◽  
Acyl Carrier Proteins ◽  
E Coli ◽  
Rtx Toxins ◽  
Wide Range ◽  
Lysine Residues ◽  
Acyl Chains

In a wide range of organisms, from bacteria to humans, numerous proteins have to be posttranslationally acylated to become biologically active. Bacterial repeats in toxin (RTX) cytolysins form a prominent group of proteins that are synthesized as inactive protoxins and undergo posttranslational acylation on ε-amino groups of two internal conserved lysine residues by co-expressed toxin-activating acyltransferases. Here, we investigated how the chemical nature, position, and number of bound acyl chains govern the activities of Bordetella pertussis adenylate cyclase toxin (CyaA), Escherichia coli α-hemolysin (HlyA), and Kingella kingae cytotoxin (RtxA). We found that the three protoxins are acylated in the same E. coli cell background by each of the CyaC, HlyC, and RtxC acyltransferases. We also noted that the acyltransferase selects from the bacterial pool of acyl–acyl carrier proteins (ACPs) an acyl chain of a specific length for covalent linkage to the protoxin. The acyltransferase also selects whether both or only one of two conserved lysine residues of the protoxin will be posttranslationally acylated. Functional assays revealed that RtxA has to be modified by 14-carbon fatty acyl chains to be biologically active, that HlyA remains active also when modified by 16-carbon acyl chains, and that CyaA is activated exclusively by 16-carbon acyl chains. These results suggest that the RTX toxin molecules are structurally adapted to the length of the acyl chains used for modification of their acylated lysine residue in the second, more conserved acylation site.

scholarly journals The Role of New Inorganic Materials in Composite Membranes for Water Disinfection

Membranes ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 101 ◽  
Author(s):  
Roberto Castro-Muñoz
Keyword(s):  
Composite Membranes ◽  
Membrane Bioreactors ◽  
Polymeric Membranes ◽  
Inorganic Materials ◽  
Water Disinfection ◽  
Biologically Active ◽  
Separation Performance ◽  
Nanofiltration Membrane ◽  
Physical And Chemical

Today, there is an increasing interest in improving the physicochemical properties of polymeric membranes by merging the membranes with different inorganic materials. These so-called composite membranes have been implemented in different membrane-based technologies (e.g., microfiltration, ultrafiltration, nanofiltration, membrane bioreactors, among others) for water treatment and disinfection. This is because such inorganic materials (such as TiO2-, ZnO-, Ag-, and Cu-based nanoparticles, carbon-based materials, to mention just a few) can improve the separation performance of membranes and also some other properties, such as antifouling, mechanical, thermal, and physical and chemical stability. Moreover, such materials display specific biological activity towards viruses, bacteria, and protozoa, showing enhanced water disinfection properties. Therefore, the aim of this review is to collect the latest advances (in the last five years) in using composite membranes and new hybrid materials for water disinfection, paying particular emphasis on relevant results and new hydride composites together with their preparation protocols. Moreover, this review addresses the main mechanism of action of different conventional and novel inorganic materials toward biologically active matter.

Anionic food color tartrazine enhances antibacterial efficacy of histatin-derived peptide DHVAR4 by fine-tuning its membrane activity

2020 ◽  
Vol 53 ◽  
Author(s):  
Maria Ricci ◽  
Kata Horváti ◽  
Tünde Juhász ◽  
Imola Szigyártó ◽  
György Török ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Bacterial Infections ◽  
Food Additives ◽  
Biologically Active ◽  
Fine Tuning ◽  
Helical Conformation ◽  
Head Group ◽  
Phosphate Ester ◽  
Host Defense Peptides ◽  
Toxic Activity

Abstract Here it is demonstrated how some anionic food additives commonly used in our diet, such as tartrazine (TZ), bind to DHVAR4, an antimicrobial peptide (AMP) derived from oral host defense peptides, resulting in significantly fostered toxic activity against both Gram-positive and Gram-negative bacteria, but not against mammalian cells. Biophysical studies on the DHVAR4–TZ interaction indicate that initially large, positively charged aggregates are formed, but in the presence of lipid bilayers, they rather associate with the membrane surface. In contrast to synergistic effects observed for mixed antibacterial compounds, this is a principally different mechanism, where TZ directly acts on the membrane-associated AMP promoting its biologically active helical conformation. Model vesicle studies show that compared to dye-free DHVAR4, peptide–TZ complexes are more prone to form H-bonds with the phosphate ester moiety of the bilayer head-group region resulting in more controlled bilayer fusion mechanism and concerted severe cell damage. AMPs are considered as promising compounds to combat formidable antibiotic-resistant bacterial infections; however, we know very little on their in vivo actions, especially on how they interact with other chemical agents. The current example illustrates how food dyes can modulate AMP activity, which is hoped to inspire improved therapies against microbial infections in the alimentary tract. Results also imply that the structure and function of natural AMPs could be manipulated by small compounds, which may also offer a new strategic concept for the future design of peptide-based antimicrobials.

scholarly journals Effect of amiloride and some of its analogues of cation transport in isolated frog skin and thin lipid membranes.

1976 ◽  
Vol 68 (1) ◽  
pp. 43-63 ◽  
Author(s):  
D J Benos ◽  
S A Simon ◽  
L J Mandel ◽  
P M Cala
Keyword(s):  
Lipid Membranes ◽  
Frog Skin ◽  
Short Circuit ◽  
Short Circuit Current ◽  
Active Species ◽  
Biologically Active ◽  
Lipid Bilayer Membranes ◽  
Inhibitory Interaction ◽  
Charged Form ◽  
Transport Site

The inhibition of short-circuit current (Isc) in isolated frog skin and the induction of surface potentials in lipid bilayer membranes produced by the diuretic drug amiloride and a number of its chemical analogues was studied. The major conclusions of our study are: (a) The charged form of amiloride is the biologically active species. (b) Both the magnitude of Isc and the amiloride inhibitory effect are sensitive to the ionic milieu bathing the isolated skin, and these two features are modulated at separate and distinct regions on the transport site. (c) Amiloride is very specific in its inhibitory interaction with the Na+ transport site since slight structural modifications can result in significant changes in drug effectiveness. We found that substitutions at pyrazine ring position 5 greatly diminish drug activity, while changes at position 6 are less drastic. Alterations in the guanidinium moiety only diminish activity if the result is a change in the spatial orientation of the amino group carrying the positive charge. (d) Amiloride can bind to and alter the charge on membrane surfaces, but this action cannot explain its highly specific effects in biological systems.

Bimodal Effect of Amphiphilic Biocide Concentrations on Fluidity of Lipid Membranes

1996 ◽  
Vol 51 (11-12) ◽  
pp. 853-858 ◽  
Author(s):  
Marian Podolak ◽  
Dariusz Man ◽  
Stanislaw Waga ◽  
Stanislaw Przestalski
Keyword(s):  
Binding Energy ◽  
Lipid Membranes ◽  
Positive Charge ◽  
Egg Yolk ◽  
Biologically Active ◽  
Double Positive ◽  
Dipole System ◽  
Monovalent Ions ◽  
Single Positive ◽  
High Concentrations

Abstract Using the spin label method (ESR) it has been shown that biologically active, amphiphilic compounds (quaternary ammonium salts -AS) containing polar heads with single and double positive charge caused, at low concentrations, decrease fluidity of liposome membranes formed with egg yolk lecithin (EYL). At higher concentrations an increase in fluidity was observed. With compounds having a single positive charge minimum fluidity of membrane structure occurs in the range of 1 to 3%, with compounds containing double positive charge -in the range of 4 -6 % . That effect does not depend on polar head size and length of alkyl chains of the AS used. Analysis of the electrostatic interaction between positive charges and dipole system suggest that at low ion concentrations the binding energy of the system increases, while it decreases at high concentrations. For the model presented, maxi­mum of binding energy of the system occurs at 3% of positive monovalent ions and at 6% of positive divalent ions admixed.

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