scholarly journals A Novel Frameshifting Inhibitor Having Antiviral Activity against Zoonotic Coronaviruses

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1639
Author(s):  
Dae-Gyun Ahn ◽  
Gun Young Yoon ◽  
Sunhee Lee ◽  
Keun Bon Ku ◽  
Chonsaeng Kim ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Drug Candidate ◽  
Replicase Gene ◽  
The Novel ◽  
Viral Propagation ◽  
Infected Cells ◽  
Repurposed Drugs ◽  
Rna Pseudoknot ◽  
Derivatives Of

Recent outbreaks of zoonotic coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have caused tremendous casualties and great economic shock. Although some repurposed drugs have shown potential therapeutic efficacy in clinical trials, specific therapeutic agents targeting coronaviruses have not yet been developed. During coronavirus replication, a replicase gene cluster, including RNA-dependent RNA polymerase (RdRp), is alternatively translated via a process called -1 programmed ribosomal frameshift (−1 PRF) by an RNA pseudoknot structure encoded in viral RNAs. The coronavirus frameshifting has been identified previously as a target for antiviral therapy. In this study, the frameshifting efficiencies of MERS-CoV, SARS-CoV and SARS-CoV-2 were determined using an in vitro −1 PRF assay system. Our group has searched approximately 9689 small molecules to identify potential −1 PRF inhibitors. Herein, we found that a novel compound, 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline (KCB261770), inhibits the frameshifting of MERS-CoV and effectively suppresses viral propagation in MERS-CoV-infected cells. The inhibitory effects of 87 derivatives of furo[2,3-b]quinolines were also examined showing less prominent inhibitory effect when compared to compound KCB261770. We demonstrated that KCB261770 inhibits the frameshifting without suppressing cap-dependent translation. Furthermore, this compound was able to inhibit the frameshifting, to some extent, of SARS-CoV and SARS-CoV-2. Therefore, the novel compound 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline may serve as a promising drug candidate to interfere with pan-coronavirus frameshifting.

Design, synthesis and antibacterial evaluation of ocotillol derivatives with polycyclic nitrogen-containing groups

2021 ◽  
Author(s):  
Yucheng Cao ◽  
Kaiyi Wang ◽  
Jiali Wang ◽  
Haoran Cheng ◽  
Mengxin Ma ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Multidrug Resistant ◽  
Inhibitory Effect ◽  
Resistant Bacteria ◽  
Design Synthesis ◽  
In Vitro Antibacterial Activity ◽  
Strong Inhibitory Effect ◽  
Hospital Acquired ◽  
Derivatives Of

Aim: With the increasing abuse of antibacterial drugs, multidrug-resistant bacteria have become a burden on human health and the healthcare system. To find alternative compounds effective against hospital-acquired methicillin-resistant Staphylococcus aureus (HA-MRSA), novel derivatives of ocotillol were synthesized. Methods & Results: Ocotillol derivatives with polycyclic nitrogen-containing groups were synthesized and evaluated for in vitro antibacterial activity. Compounds 36–39 exhibited potent antibacterial activity against hospital-acquired MRSA, with MIC = 8–64 μg/ml. Additionally, a combination of compound 37 and the commercially available antibiotic kanamycin showed synergistic inhibitory effects, with a fractional inhibitory concentration index of ≤0.375. Conclusion: Compound 37 has a strong inhibitory effect, and this derivative has potential for use as a pharmacological tool to explore antibacterial mechanisms.

scholarly journals Aspergillus flavus as a Model System to Test the Biological Activity of Botanicals: An Example on Citrullus colocynthis L. Schrad. Organic Extracts

Toxins ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 286 ◽  
Author(s):  
Francesca Degola ◽  
Belsem Marzouk ◽  
Antonella Gori ◽  
Cecilia Brunetti ◽  
Lucia Dramis ◽  
...  
Keyword(s):  
Biological Activity ◽  
Aspergillus Flavus ◽  
Folk Medicine ◽  
Inhibitory Effect ◽  
Phytopathogenic Fungus ◽  
Citrullus Colocynthis ◽  
Desert Areas ◽  
Derivatives Of ◽  
Stem Leaf

Citrullus colocynthis L. Schrader is an annual plant belonging to the Cucurbitaceae family, widely distributed in the desert areas of the Mediterranean basin. Many pharmacological properties (anti-inflammatory, anti-diabetic, analgesic, anti-epileptic) are ascribed to different organs of this plant; extracts and derivatives of C. colocynthis are used in folk Berber medicine for the treatment of numerous diseases—such as rheumatism arthritis, hypertension bronchitis, mastitis, and even cancer. Clinical studies aimed at confirming the chemical and biological bases of pharmacological activity assigned to many plant/herb extracts used in folk medicine often rely on results obtained from laboratory preliminary tests. We investigated the biological activity of some C. colocynthis stem, leaf, and root extracts on the mycotoxigenic and phytopathogenic fungus Aspergillus flavus, testing a possible correlation between the inhibitory effect on aflatoxin biosynthesis, the phytochemical composition of extracts, and their in vitro antioxidant capacities.

scholarly journals Glutathione S-transferase pi as a target for tricyclic antidepressants in human brain.

2004 ◽  
Vol 51 (1) ◽  
pp. 207-212 ◽  
Author(s):  
Anna Barańczyk-Kuźma ◽  
Magdalena Kuźma ◽  
Marzena Gutowicz ◽  
Beata Kaźmierczak ◽  
Jacek Sawicki
Keyword(s):  
Human Brain ◽  
Tricyclic Antidepressants ◽  
Inhibitory Effect ◽  
Glutathione S Transferase ◽  
Brain Localization ◽  
Vitro Effect ◽  
Derivatives Of ◽  
The Brain ◽  
Noncompetitive Inhibitors

GST pi, the main glutathione S-transferase isoform present in the human brain, was isolated from various regions of the brain and the in vitro effect of tricyclic antidepressants on its activity was studied. The results indicated that amitripyline and doxepin--derivatives of dibenzcycloheptadiene, as well as imipramine and clomipramine--derivatives of dibenzazepine, inhibit the activity of GST pi from frontal and parietal cortex, hippocampus and brain stem. All these tricyclics are noncompetitive inhibitors of the enzyme with respect to reduced glutathione and noncompetitive (amitripyline, doxepin) or uncompetitive (imipramine, clomipramine) with respect to the electrophilic substrate. Their inhibitory effect is reversible and it depends on the chemical structure of the tricyclic antidepressants rather than on the brain localization of the enzyme. We conclude that the interaction between GST pi and the drugs may reduce their availability in the brain and thus affect their therapeutic activity. On the other hand, tricyclic antidepressants may decrease the efficiency of the enzymatic barrier formed by GST and increase the exposure of brain to toxic electrophiles. Reactive electrophiles not inactivated by GST may contribute in adverse effects caused by these drugs.

scholarly journals Protective Role of Combined Polyphenols and Micronutrients against Influenza A Virus and SARS-CoV-2 Infection In Vitro

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1721
Author(s):  
Marta De Angelis ◽  
David Della-Morte ◽  
Gabriele Buttinelli ◽  
Angela Di Martino ◽  
Francesca Pacifici ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Influenza A ◽  
Viral Proteins ◽  
Antiviral Effect ◽  
Inhibitory Effect ◽  
Protective Role ◽  
Virus Infections ◽  
Infected Cells ◽  
Respiratory Virus Infections

Polyphenols have been widely studied for their antiviral effect against respiratory virus infections. Among these, resveratrol (RV) has been demonstrated to inhibit influenza virus replication and more recently, it has been tested together with pterostilbene against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In the present work, we evaluated the antiviral activity of polydatin, an RV precursor, and a mixture of polyphenols and other micronutrients, named A5+, against influenza virus and SARS-CoV-2 infections. To this end, we infected Vero E6 cells and analyzed the replication of both respiratory viruses in terms of viral proteins synthesis and viral titration. We demonstrated that A5+ showed a higher efficacy in inhibiting both influenza virus and SARS-CoV-2 infections compared to polydatin treatment alone. Indeed, post infection treatment significantly decreased viral proteins expression and viral release, probably by interfering with any step of virus replicative cycle. Intriguingly, A5+ treatment strongly reduced IL-6 cytokine production in influenza virus-infected cells, suggesting its potential anti-inflammatory properties during the infection. Overall, these results demonstrate the synergic and innovative antiviral efficacy of A5+ mixture, although further studies are needed to clarify the mechanisms underlying its inhibitory effect.

scholarly journals Comparisons of In Vivo and In Vitro Opioid Effects of Newly Synthesized 14-Methoxycodeine-6-O-sulfate and Codeine-6-O-sulfate

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1370 ◽  
Author(s):  
Ferenc Zádor ◽  
Amir Mohammadzadeh ◽  
Mihály Balogh ◽  
Zoltán S. Zádori ◽  
Kornél Király ◽  
...  
Keyword(s):  
Opioid Receptor ◽  
Antinociceptive Effect ◽  
Gastrointestinal Transit ◽  
Inhibitory Effect ◽  
In Vitro Tests ◽  
Tail Flick ◽  
The Novel ◽  
Gastrointestinal Side Effects

The present work represents the in vitro (potency, affinity, efficacy) and in vivo (antinociception, constipation) opioid pharmacology of the novel compound 14-methoxycodeine-6-O-sulfate (14-OMeC6SU), compared to the reference compounds codeine-6-O-sulfate (C6SU), codeine and morphine. Based on in vitro tests (mouse and rat vas deferens, receptor binding and [35S]GTPγS activation assays), 14-OMeC6SU has µ-opioid receptor-mediated activity, displaying higher affinity, potency and efficacy than the parent compounds. In rats, 14-OMeC6SU showed stronger antinociceptive effect in the tail-flick assay than codeine and was equipotent to morphine, whereas C6SU was less efficacious after subcutaneous (s.c.) administration. Following intracerebroventricular injection, 14-OMeC6SU was more potent than morphine. In the Complete Freund’s Adjuvant-induced inflammatory hyperalgesia, 14-OMeC6SU and C6SU in s.c. doses up to 6.1 and 13.2 µmol/kg, respectively, showed peripheral antihyperalgesic effect, because co-administered naloxone methiodide, a peripherally acting opioid receptor antagonist antagonized the measured antihyperalgesia. In addition, s.c. C6SU showed less pronounced inhibitory effect on the gastrointestinal transit than 14-OMeC6SU, codeine and morphine. This study provides first evidence that 14-OMeC6SU is more effective than codeine or C6SU in vitro and in vivo. Furthermore, despite C6SU peripheral antihyperalgesic effects with less gastrointestinal side effects the superiority of 14-OMeC6SU was obvious throughout the present study.

Anti-Human Immunodeficiency Virus (HIV) Activity of the Novel Antiviral Antibiotic Quartromicins which Enhance Inhibitory Effect of 3′-azido-2′,3′-dideoxythymidine (AZT) in vitro

1992 ◽  
Vol 3 (6) ◽  
pp. 345-349 ◽  
Author(s):  
A. Tanabe-Tochikura ◽  
H. Nakashima ◽  
T. Murakami ◽  
O. Tenmyo ◽  
T. Oki ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Specific Antigen ◽  
Antigen Expression ◽  
Antiviral Effect ◽  
Inhibitory Effect ◽  
Reverse Transcriptase Activity ◽  
The Novel ◽  
Avian Myeloblastosis Virus ◽  
Immunodeficiency Virus

Novel antiviral antibiotic quartromicins A1 and D1, isolated from Amycolatopsis orientalis, significantly inhibited human immunodeficiency virus (HIV)-induced cytopathic effect and virus specific antigen expression at concentrations of 25–100 μg ml−1 In MT-4 cells infected with HTLV-IIIB. The reverse transcriptase activity of disrupted HTLV-IIIB particles, recombinant HIV-1 enzyme, and purified avian myeloblastosis virus (AMV) enzyme were also significantly inhibited by quartromicins A1 and D1. The combined antiviral effect of quartromicin A1 and AZT on the replication of HIV in MT-4 cells was also examined. Quartromicin A1 synergistically enhanced the inhibitory effect of AZT as revealed by HIV-specific antigen expression.

scholarly journals Synthesis of a Novel α-Glucosyl Ginsenoside F1 by Cyclodextrin Glucanotransferase and Its In Vitro Cosmetic Applications

Biomolecules ◽  
2018 ◽  
Vol 8 (4) ◽  
pp. 142 ◽  
Author(s):  
Seong Moon ◽  
Hye Lee ◽  
Ramya Mathiyalagan ◽  
Yu Kim ◽  
Dong Yang ◽  
...  
Keyword(s):  
Quantum Coherence ◽  
Dermal Fibroblast ◽  
Multiple Bond ◽  
Proton Nuclear Magnetic Resonance ◽  
Cyclodextrin Glucanotransferase ◽  
The Novel ◽  
Pharmacological Activities ◽  
Matrix Metalloproteinase 1 ◽  
Derivatives Of

Ginsenosides from Panax ginseng (Korean ginseng) are unique triterpenoidal saponins that are considered to be responsible for most of the pharmacological activities of P. ginseng. However, the various linkage positions cause different pharmacological activities. In this context, we aimed to synthesize new derivatives of ginsenosides with unusual linkages that show enhanced pharmacological activities. Novel α-glycosylated derivatives of ginsenoside F1 were synthesized from transglycosylation reactions of dextrin (sugar donor) and ginsenoside F1 (acceptor) by the successive actions of Toruzyme®3.0L, a cyclodextrin glucanotransferase. One of the resultant products was isolated and identified as (20S)-3β,6α,12β-trihydroxydammar-24ene-(20-O-β-D-glucopyranosyl-(1→2)-α-D-glucopyranoside) by various spectroscopic characterization techniques of fast atom bombardment-mass spectrometry (FAB-MS), infrared spectroscopy (IR), proton-nuclear magnetic resonance (1H-NMR), 13C-NMR, gradient heteronuclear single quantum coherence (gHSQC), and gradient heteronuclear multiple bond coherence (gHMBC). As expected, the novel α-glycosylated ginsenoside F1 (G1-F1) exhibited increased solubility, lower cytotoxicity toward human dermal fibroblast cells (HDF), and higher tyrosinase activity and ultraviolet A (UVA)-induced inhibitory activity against matrix metalloproteinase-1 (MMP-1) than ginsenoside F1. Since F1 has been reported as an antiaging and antioxidant agent, the enhanced efficacies of the novel α-glycosylated ginsenoside F1 suggest that it might be useful in cosmetic applications after screening.

scholarly journals Novel Endochin-Like Quinolones Exhibit Potent In Vitro Activity against Plasmodium knowlesi but Do Not Synergize with Proguanil

2020 ◽  
Vol 64 (5) ◽  
Author(s):  
Donelly A. van Schalkwyk ◽  
Michael K. Riscoe ◽  
Sovitj Pou ◽  
Rolf W. Winter ◽  
Aaron Nilsen ◽  
...  
Keyword(s):  
Plasmodium Knowlesi ◽  
Ex Vivo ◽  
Life Cycles ◽  
The Novel ◽  
Important Species ◽  
Content Type ◽  
Ongoing Development ◽  
Multiple Species ◽  
Derivatives Of

ABSTRACT Quinolones, such as the antimalarial atovaquone, are inhibitors of the malarial mitochondrial cytochrome bc1 complex, a target critical to the survival of both liver- and blood-stage parasites, making these drugs useful as both prophylaxis and treatment. Recently, several derivatives of endochin have been optimized to produce novel quinolones that are active in vitro and in animal models. While these quinolones exhibit potent ex vivo activity against Plasmodium falciparum and Plasmodium vivax, their activity against the zoonotic agent Plasmodium knowlesi is unknown. We screened several of these novel endochin-like quinolones (ELQs) for their activity against P. knowlesi in vitro and compared this with their activity against P. falciparum tested under identical conditions. We demonstrated that ELQs are potent against P. knowlesi (50% effective concentration, <117 nM) and equally effective against P. falciparum. We then screened selected quinolones and partner drugs using a longer exposure (2.5 life cycles) and found that proguanil is 10-fold less potent against P. knowlesi than P. falciparum, while the quinolones demonstrate similar potency. Finally, we used isobologram analysis to compare combinations of the ELQs with either proguanil or atovaquone. We show that all quinolone combinations with proguanil are synergistic against P. falciparum. However, against P. knowlesi, no evidence of synergy between proguanil and the quinolones was found. Importantly, the combination of the novel quinolone ELQ-300 with atovaquone was synergistic against both species. Our data identify potentially important species differences in proguanil susceptibility and in the interaction of proguanil with quinolones and support the ongoing development of novel quinolones as potent antimalarials that target multiple species.

scholarly journals The biosynthesis of sulphogalactosyldiacylglycerol of rat brain in vitro

1977 ◽  
Vol 166 (3) ◽  
pp. 429-435 ◽  
Author(s):  
G. Subba Rao ◽  
Leonard N. Norcia ◽  
Joanne Pieringer ◽  
Ronald A. Pieringer
Keyword(s):  
Enzyme Activity ◽  
Rat Brain ◽  
Enzyme Preparation ◽  
Microsomal Fraction ◽  
Inhibitory Effect ◽  
Subcellular Fractions ◽  
Triton X ◽  
Derivatives Of

Triton X-100 extracts of rat brain microsomal fraction catalyse the formation of sulphogalactosyldiacylglycerol from galactosyldiacylglycerol and adenosine 3′-phosphate 5′-sulphatophosphate. Of the various subcellular fractions of brain assayed, the microsomal fraction contained most (79%) of the adenosine 3′-phosphate 5′-sulphatophosphate–galactosyldiacylglycerol sulphotransferase activity. The enzyme activity was stimulated by Triton X-100 and showed linearity with increasing time, concentrations of enzyme and added substrates. ATP and KF prolonged the linearity of the activity with time, but ATP had an overall inhibitory effect on the sulphotransferase. Both ATP and KF inhibit the degradation of adenosine 3′-phosphate 5′-sulphatophosphate, which probably causes the increased linearity of the sulphotransferase reaction with time. The enzyme preparation did not catalyse the transfer of sulphate from adenosine 3′-phosphate 5′-sulphatophosphate to either cholesterol or galabiosyldiacylglycerol (galactosylgalactosyldiacylglycerol). Significant differences between the formation of sulphogalactosyldiacylglycerol and cerebroside sulphate catalysed by the same enzyme preparation were noted. ATP and Mg2+ strongly inhibit the formation of sulphogalactosyldiacylglycerol but equally strongly stimulate the synthesis of cerebroside sulphate. The apparent Km for galactosyldiacylglycerol is 200μm, and that for cerebroside is 45μm. Galactosyldiacylglycerol and cerebroside are mutually inhibitory toward the synthesis of sulphated derivatives of each. These data do not necessarily lead to the conclusion that two sulphotransferases are present, but they do indicate a possible means of controlling the synthesis of these two sulpholipids.

scholarly journals Activation ofTomato Bushy Stunt VirusRNA-Dependent RNA Polymerase by Cellular Heat Shock Protein 70 Is Enhanced by PhospholipidsIn Vitro

2015 ◽  
Vol 89 (10) ◽  
pp. 5714-5723 ◽  
Author(s):  
Judit Pogany ◽  
Peter D. Nagy
Keyword(s):  
Rna Polymerase ◽  
Rna Synthesis ◽  
Inhibitory Effect ◽  
Viral Rna ◽  
Infected Cells ◽  
Membrane Bound ◽  
Replicase Complex ◽  
Rna Interaction ◽  
Positive Strand Rna

ABSTRACTSimilar to other positive-strand RNA viruses, tombusviruses are replicated by the membrane-bound viral replicase complex (VRC). The VRC consists of the p92 virus-coded RNA-dependent RNA polymerase (RdRp), the viral p33 RNA chaperone, and several co-opted host proteins. In order to become a functional RdRp after its translation, the p92 replication protein should be incorporated into the VRC, followed by its activation. We have previously shown in a cell-free yeast extract-based assay that the activation of theTomato bushy stunt virus(TBSV) RdRp requires a soluble host factor(s). In this article, we identify the cellular heat shock protein 70 (Hsp70) as the co-opted host factor required for the activation of an N-terminally truncated recombinant TBSV RdRp. In addition, small-molecule-based blocking of Hsp70 function inhibits RNA synthesis by the tombusvirus RdRpin vitro. Furthermore, we show that neutral phospholipids, namely, phosphatidylethanolamine (PE) and phosphatidylcholine (PC), enhance RdRp activationin vitro. In contrast, phosphatidylglycerol (PG) shows a strong and dominant inhibitory effect onin vitroRdRp activation. We also demonstrate that PE and PC stimulate RdRp-viral plus-strand RNA [(+)RNA] interaction, while PG inhibits the binding of the viral RNA to the RdRp. Based on the stimulatory versus inhibitory roles of various phospholipids in tombusvirus RdRp activation, we propose that the lipid composition of targeted subcellular membranes might be utilized by tombusviruses to regulate new VRC assembly during the course of infection.IMPORTANCEThe virus-coded RNA-dependent RNA polymerase (RdRp), which is responsible for synthesizing the viral RNA progeny in infected cells of several positive-strand RNA viruses, is initially inactive. This strategy is likely to avoid viral RNA synthesis in the cytosol that would rapidly lead to induction of RNA-triggered cellular antiviral responses. During the assembly of the membrane-bound replicase complex, the viral RdRp becomes activated through an incompletely understood process that makes the RdRp capable of RNA synthesis. By using TBSV RdRp, we show that the co-opted cellular Hsp70 chaperone and neutral phospholipids facilitate RdRp activationin vitro. In contrast, phosphatidylglycerol (PG) has a dominant inhibitory effect onin vitroRdRp activation and RdRp-viral RNA interaction, suggesting that the membranous microdomain surrounding the RdRp greatly affects its ability for RNA synthesis. Thus, the activation of the viral RdRp likely depends on multiple host components in infected cells.

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