scholarly journals Aptamers in the Treatment of Bacterial Infections: Problems and Prospects

2016 ◽  
Vol 71 (5) ◽  
pp. 350-358
Author(s):  
N. A. Zeninskaya ◽  
A. V. Kolesnikov ◽  
A. K. Ryabko ◽  
I. G. Shemyakin ◽  
I. A. Dyatlov ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput Screening ◽  
Bacterial Infections ◽  
Point Of View ◽  
Aptamer Selection ◽  
Wide Range ◽  
Therapeutic Molecules ◽  
Molecular Selection ◽  
The Stability

Aptamers are short single-stranded oligonucleotides which are selected via targeted chemical evolution in vitro to bind a molecular target of interest. The aptamer selection technology is designated as SELEX (Systematic evolution of ligands by exponential enrichment). SELEX enables isolation of oligonucleotide aptamers binding a wide range of targets of interest with little respect for their nature and molecular weight. A number of applications of aptamer selection were developed ranging from biosensor technologies to antitumor drug discovery. First aptamer-based pharmaceutical (Macugen) was approved by FDA for clinical use in 2004, and since then more than ten aptamer-based drugs undergo various phases of clinical trials. From the medicinal chemist’s point of view, aptamers represent a new class of molecules suitable for the development of new therapeutics. Due to the stability, relative synthesis simplicity, and development of advanced strategies of target specific molecular selection, aptamers attract increased attention of drug discovery community. Difficulties of the development of next-generation antibiotics basing on the conventional basis of combinatorial chemistry and high-throughput screening have also amplified the interest to aptamer-based therapeutic candidates. The present article reviews the investigations focused on the development of antibacterial aptamers and discusses the potential and current limitations of the use of this type of therapeutic molecules.

scholarly journals Antibacterial Activity of Rationally Designed Antimicrobial Peptides

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Marius B. Tincho ◽  
Thureyah Morris ◽  
Mervin Meyer ◽  
Ashley Pretorius
Keyword(s):  
Antibacterial Activity ◽  
Infectious Diseases ◽  
Antimicrobial Peptides ◽  
Bacterial Infections ◽  
Current Treatment ◽  
Resistant Bacteria ◽  
Treatment Regimens ◽  
Wide Range ◽  
Therapeutic Molecules

Many infectious diseases are still prevalent in the world’s populations since no effective treatments are available to eradicate them. The reasons may either be the antibiotic resistance towards the available therapeutic molecules or the slow rate of producing adequate therapeutic regimens to tackle the rapid growth of new infectious diseases, as well as the toxicity of current treatment regimens. Due to these reasons, there is a need to seek and develop novel therapeutic regimens to reduce the rapid scale of bacterial infections. Antimicrobial Peptides (AMPs) are components of the first line of defense for prokaryotes and eukaryotes and have a wide range of activities against Gram-negative and Gram-positive bacteria, fungi, cancer cells, and protozoa, as well as viruses. In this study, peptides which were initially identified for their HIV inhibitory activity were further screened for antibacterial activity through determination of their kinetics as well as their cytotoxicity. From the results obtained, the MICs of two AMPs (Molecule 3 and Molecule 7) were 12.5 μg/ml for K. pneumoniae (ATCC 700603) and 6.25 μg/ml for P. aeruginosa (ATCC 22108). The two AMPs killed these bacteria rapidly in vitro, preventing bacterial growth within few hours of treatment. Furthermore, the cytotoxic activity of these two peptides was significantly low, even at an AMP concentration of 100 μg/ml. These results revealed that Molecule 3 and 7 have great potential as antibacterial drugs or could serve as lead compounds in the design of therapeutic regimens for the treatment of antibiotic-resistant bacteria.

scholarly journals Insights into the Antioxidant Mechanism of Newly Synthesized Benzoxazinic Nitrones: In Vitro and In Silico Studies with DPPH Model Radical

Antioxidants ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1224
Author(s):  
Stefania Marano ◽  
Cristina Minnelli ◽  
Lorenzo Ripani ◽  
Massimo Marcaccio ◽  
Emiliano Laudadio ◽  
...  
Keyword(s):  
Antioxidant Activity ◽  
Epr Spectroscopy ◽  
Point Of View ◽  
Uv Spectrophotometry ◽  
Design And Synthesis ◽  
Antioxidant Mechanism ◽  
Primary Mechanism ◽  
In Silico Studies ◽  
Wide Range

Synthetic nitrone spin-traps are being explored as therapeutic agents for the treatment of a wide range of oxidative stress-related pathologies, including but not limited to stroke, cancer, cardiovascular, and neurodegenerative diseases. In this context, increasing efforts are currently being made to the design and synthesis of new nitrone-based compounds with enhanced efficacy. The most researched nitrones are surely the ones related to α-phenyl-tert-butylnitrone (PBN) and 5,5-dimethyl-1-pyrroline N-oxide (DMPO) derivatives, which have shown to possess potent biological activity in many experimental animal models. However, more recently, nitrones with a benzoxazinic structure (3-aryl-2H-benzo[1,4]oxazin-N-oxides) have been demonstrated to have superior antioxidant activity compared to PBN. In this study, two new benzoxazinic nitrones bearing an electron-withdrawing methoxycarbonyl group on the benzo moiety (in para and meta positions respect to the nitronyl function) were synthesized. Their in vitro antioxidant activity was evaluated by two cellular-based assays (inhibition of AAPH-induced human erythrocyte hemolysis and cell death in human retinal pigmented epithelium (ARPE-19) cells) and a chemical approach by means of the α,α-diphenyl-β-picrylhydrazyl (DPPH) scavenging assay, using both electron paramagnetic resonance (EPR) spectroscopy and UV spectrophotometry. A computational approach was also used to investigate their potential primary mechanism of antioxidant action, as well as to rationalize the effect of functionalization on the nitrones reactivity toward DPPH, chosen as model radical in this study. Further insights were also gathered by exploring the nitrone electrochemical properties via cyclic voltammetry and by studying their kinetic behavior by means of EPR spectroscopy. Results showed that the introduction of an electron-withdrawing group in the phenyl moiety in the para position significantly increased the antioxidant capacity of benzoxazinic nitrones both in cell and cell-free systems. From the mechanistic point of view, the calculated results closely matched the experimental findings, strongly suggesting that the H-atom transfer (HAT) is likely to be the primary mechanism in the DPPH quenching.

scholarly journals No-z Model for Magnetic Fields of Different Astrophysical Objects and Stability of the Solutions

Data ◽  
2021 ◽  
Vol 6 (1) ◽  
pp. 4
Author(s):  
Evgeny Mikhailov ◽  
Daniela Boneva ◽  
Maria Pashentseva
Keyword(s):  
Magnetic Field ◽  
Magnetic Fields ◽  
Large Scale ◽  
Point Of View ◽  
Accretion Discs ◽  
Wide Range ◽  
Astrophysical Objects ◽  
Alpha Effect ◽  
The Stability ◽  
The Magnetic Field

A wide range of astrophysical objects, such as the Sun, galaxies, stars, planets, accretion discs etc., have large-scale magnetic fields. Their generation is often based on the dynamo mechanism, which is connected with joint action of the alpha-effect and differential rotation. They compete with the turbulent diffusion. If the dynamo is intensive enough, the magnetic field grows, else it decays. The magnetic field evolution is described by Steenbeck—Krause—Raedler equations, which are quite difficult to be solved. So, for different objects, specific two-dimensional models are used. As for thin discs (this shape corresponds to galaxies and accretion discs), usually, no-z approximation is used. Some of the partial derivatives are changed by the algebraic expressions, and the solenoidality condition is taken into account as well. The field generation is restricted by the equipartition value and saturates if the field becomes comparable with it. From the point of view of mathematical physics, they can be characterized as stable points of the equations. The field can come to these values monotonously or have oscillations. It depends on the type of the stability of these points, whether it is a node or focus. Here, we study the stability of such points and give examples for astrophysical applications.

Biocatalytic synthesis of terpene esters and their biological activity in human glioma cells

2021 ◽  
Vol 22 ◽  
Author(s):  
Mateusz Kutyła ◽  
Aleksandra Maciejczyk ◽  
Mariusz Trytek ◽  
Joanna Jakubowicz-Gil
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
Fold Increase ◽  
Point Of View ◽  
Terpene Alcohols ◽  
Human Glioblastoma Multiforme ◽  
Anti Cancer ◽  
Therapeutic Molecules ◽  
Resistance To Chemotherapy

Background: Gliomas are highly malignant brain tumors with high resistance to chemotherapy. Therefore, investigations of new therapeutic molecules with high anti-glioma activity are of great importance. Objective: In this work, biocatalytic esterification of terpene alcohols with proven anti-cancer activity was performed to enhance their potency to induce cell death in human glioblastoma multiforme T98G and anaplastic astrocytoma MOGGCCM cell lines in vitro. Method and Results: We used primary terpene alcohols and carboxylic acids with a length of two to nine carbon atoms. The structure of the drinks influenced the esterification efficiency, which decreased in the following order: monocyclic > linear > bicyclic. Terpene alcohols and their esters only induced apoptotic cell death, which is highly desirable from a therapeutic point of view but did not induce autophagy and necrosis. The esterification of perillyl alcohol with butyric acid caused a 4-fold increase in cell death induction in the T98G line. Citronellol valerate, caprylate, and pelargonate and myrtenol butyrate, caprylate, and pelargonate also showed higher activity than their alcohol precursors. Conclusion: We have herein shown that esterification of natural alcohols by biocatalysis can improve the activity for other compounds investigated for their anti-glioma activity.

scholarly journals The Influence of In Vitro Gastrointestinal Digestion on the Chemical Composition and Antioxidant and Enzyme Inhibitory Capacities of Carob Liqueurs Obtained with Different Elaboration Techniques

Antioxidants ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 563 ◽  
Author(s):  
Raquel Rodríguez-Solana ◽  
Natacha Coelho ◽  
Antonio Santos-Rufo ◽  
Sandra Gonçalves ◽  
Efrén Pérez-Santín ◽  
...  
Keyword(s):  
Chemical Composition ◽  
Alcoholic Beverage ◽  
Total Phenolic ◽  
Gastrointestinal Digestion ◽  
Antidiabetic Therapy ◽  
Wide Range ◽  
Production Techniques ◽  
Inhibitory Potential ◽  
The Stability

Carob liqueur is a traditional Mediterranean alcoholic beverage obtained via a wide range of production techniques contributing to the different organoleptic attributes of the final product. The aim of this research was to evaluate the stability of the chemical composition and biological capacities (antioxidant and enzyme inhibition) under in vitro simulated gastrointestinal digestion of liqueurs prepared by flavouring the fig spirit with carob pulp by maceration, distillation, percolation, or aqueous and hydro-alcoholic infusions. For this purpose, the phenolic and furanic compositions, the total phenolic (TPC) and flavonoid (TFC) contents, antioxidant capacity (AC), and enzyme inhibitory potential against acethylcholinesterase, tyrosinase, α-glucosidase and α-amylase enzymes were evaluated. The content of gallic acid decreased after gastrointestinal digestion, while TPC, TFC, and AC significantly increased after each digestion phase. Overall, no significantly different enzyme inhibitions (p < 0.05) were observed among digested liqueurs, with moderate inhibition against acethylcholinesterase and tyrosinase (enzymes related with neurodegenerative diseases), and potent and low inhibitory capacities for α-glucosidase and α-amylase, respectively (ideal conditions employed in antidiabetic therapy). The study indicates that hydro-alcoholic infusion and maceration were the most appropriate methods to obtain liqueurs with higher values of the aforementioned parameters and safe levels of toxic furanics.

scholarly journals In Vitro and In Vivo Antibacterial Activities of SM-216601, a New Broad-Spectrum Parenteral Carbapenem

2005 ◽  
Vol 49 (10) ◽  
pp. 4185-4196 ◽  
Author(s):  
Yutaka Ueda ◽  
Katsunori Kanazawa ◽  
Ken Eguchi ◽  
Koji Takemoto ◽  
Yoshiro Eriguchi ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Antibacterial Activities ◽  
Multiresistant Pathogens ◽  
E Coli ◽  
Wide Range ◽  
Agar Dilution ◽  
Resistant Strains ◽  
Mrsa Strains

ABSTRACT SM-216601 is a novel parenteral 1β-methylcarbapenem. In agar dilution susceptibility testing, the MIC of SM-216601 for 90% of the methicillin-resistant Staphylococcus aureus (MRSA) strains tested (MIC90) was 2 μg/ml, which was comparable to those of vancomycin and linezolid. SM-216601 was also very potent against Enterococcus faecium, including vancomycin-resistant strains (MIC90 = 8 μg/ml). SM-216601 exhibited potent activity against penicillin-resistant Streptococcus pneumoniae, ampicillin-resistant Haemophilus influenzae, Moraxella catarrhalis, Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis, with MIC90s of less than 0.5 μg/ml, and intermediate activity against Citrobacter freundii, Enterobacter cloacae, Serratia marcescens, and Pseudomonas aeruginosa. The therapeutic efficacy of SM-216601 against experimentally induced infections in mice caused by S. aureus, E. faecium, E. coli, and P. aeruginosa reflected its in vitro activity and plasma level. Thus, SM-216601 is a promising candidate for nosocomial bacterial infections caused by a wide range of gram-positive and gram-negative bacteria, including multiresistant pathogens.

scholarly journals Novel Approach for Characterizing Ubiquitin E3 Ligase Function

2010 ◽  
Vol 15 (10) ◽  
pp. 1220-1228 ◽  
Author(s):  
Jeffrey G. Marblestone ◽  
K. G. Suresh Kumar ◽  
Michael J. Eddins ◽  
Craig A. Leach ◽  
David E. Sterner ◽  
...  
Keyword(s):  
Drug Discovery ◽  
High Throughput Screening ◽  
E3 Ligase ◽  
Cost Effective ◽  
Ubiquitin Proteasome System ◽  
Dependent Manner ◽  
Ubiquitin Chain ◽  
E3 Ligases ◽  
Effective Manner ◽  
Wide Range

The ubiquitin-proteasome system is central to the regulation of numerous cellular events, and dysregulation may lead to disease pathogenesis. E3 ubiquitin ligases typically function in concert with E1 and E2 enzymes to recruit specific substrates, thereby coordinating their ubiquitylation and subsequent proteasomal degradation or cellular activity. E3 ligases have been implicated in a wide range of pathologies, and monitoring their activity in a rapid and cost-effective manner would be advantageous in drug discovery. The relative lack of high-throughput screening (HTS)–compliant E3 ligase assays has significantly hindered the discovery of E3 inhibitors. Herein, the authors describe a novel HTS-compliant E3 ligase assay platform that takes advantage of a ubiquitin binding domain’s inherent affinity for polyubiquitin chains, permitting the analysis of ubiquitin chain formation in an E3 ligase-dependent manner. This assay has been used successfully with members of both the RING and HECT families, demonstrating the platform’s broad utility for analyzing a wide range of E3 ligases. The utility of the assay platform is demonstrated by the identification of inhibitors of the E3 ligase CARP2. As the number of E3 ligases associated with various disease states increases, the ability to quantitate the activity of these enzymes in an expeditious manner becomes imperative in drug discovery.

scholarly journals Recent Advances in In-Vitro Assays for Type 2 Diabetes Mellitus: An Overview

2020 ◽  
Vol 16 (1) ◽  
pp. 13-23
Author(s):  
Nazmina Vhora ◽  
Ujjal Naskar ◽  
Aishwarya Hiray ◽  
Abhijeet S. Kate ◽  
Alok Jain
Keyword(s):  
Type 2 Diabetes ◽  
Drug Discovery ◽  
High Throughput ◽  
High Throughput Screening ◽  
Antidiabetic Activity ◽  
Screening Methods ◽  
Selection Of

BACKGROUND: A higher rate of attenuation of molecules in drug discovery has enabled pharmaceutical companies to enhance the efficiency of their hit identification and lead optimization. Selection and development of appropriate in-vitro and in-vivo strategies may improve this process as primary and secondary screening utilize both strategies. In-vivo approaches are too relentless and expensive for assessing hits. Therefore, it has become indispensable to develop and implement suitable in-vitro screening methods to execute the required activities and meet the respective targets. However, the selection of an appropriate in-vitro assay for specific evaluation of cellular activity is no trivial task. It requires thorough investigation of the various parameters involved. AIM: In this review, we aim to discuss in-vitro assays for type 2 diabetes (T2D), which have been utilized extensively by researchers over the last five years, including target-based, non-target based, low-throughput, and high-throughput screening assays. METHODS: The literature search was conducted using databases including Scifinder, PubMed, ScienceDirect, and Google Scholar to find the significant published articles. DISCUSSION and CONCLUSION: The accuracy and relevance of in-vitro assays have a significant impact on the drug discovery process for T2D, especially in assessing the antidiabetic activity of compounds and identifying the site of effect in high-throughput screening. The report reviews the advantages, limitations, quality parameters, and applications of the probed invitro assays, and compares them with one another to enable the selection of the optimal method for any purpose. The information on these assays will accelerate numerous procedures in the drug development process with consistent quality and accuracy.

scholarly journals Assessing the stability of Pd-exchanged sites in zeolites with the aid of a high throughput quantum chemistry workflow

2021 ◽  
Author(s):  
Hassan Aljama ◽  
Martin Head-Gordon ◽  
Alexis Bell
Keyword(s):  
High Throughput ◽  
High Throughput Screening ◽  
Active Sites ◽  
Density Functional ◽  
Functional Materials ◽  
No Adsorption ◽  
Functional Theory ◽  
Wide Range ◽  
The Stability ◽  
Shed Light

Abstract Cation exchanged-zeolites are functional materials with a wide range of applications from catalysis to sorbents. They present a challenge for computational studies using density functional theory due to the numerous possible active sites. From Al configuration, to placement of extra framework cation(s), to potentially different oxidation states of the cation, accounting for all these possibilities is not trivial. To make the number of calculations more tractable, most studies focus on a few active sites. We attempt to go beyond these limitations by implementing a workflow for a high throughput screening, designed to systematize the problem and exhaustively search for feasible active sites. We use Pd-exchanged CHA and BEA to illustrate the approach. After conducting thousands of individual calculations, we identify the sites most favorable for the Pd cation and discuss the results in detail. The high throughput screening identifies many energetically favorable sites that are non-trivial. Lastly, we employ these results to examine NO adsorption in Pd-exchanged CHA, which is a promising passive NOx adsorbent (PNA) during the cold start of automobiles. The results shed light on critical active sites for NOx capture that were not previously studied.

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