scholarly journals The Effect of a Synthetic Estrogen, Ethinylestradiol, on the hERG Block by E-4031

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1385
Author(s):  
Fumiya Tamura ◽  
Shintaro Sugimoto ◽  
Mana Sugimoto ◽  
Kazuho Sakamoto ◽  
Masahiko Yamaguchi ◽  
...  
Keyword(s):  
Ventricular Arrhythmias ◽  
Qt Prolongation ◽  
Drug Binding ◽  
Herg Channel ◽  
Drug Binding Site ◽  
Synthetic Estrogen ◽  
Synthetic Estrogens ◽  
Herg Current ◽  
Channel Currents ◽  
Kinetics Of

Inhibition of K+-conductance through the human ether-a-go-go related gene (hERG) channel leads to QT prolongation and is associated with cardiac arrhythmias. We previously reported that physiological concentrations of some estrogens partially suppress the hERG channel currents by interacting with the S6 residue F656 and increase the sensitivity of hERG blockade by E-4031. Although these studies suggested that clinically used synthetic estrogens with similar structures have the marked potential to alter hERG functions, the hERG interactions with synthetic estrogens have not been assessed. We therefore examined whether ethinylestradiol (EE2), a synthetic estrogen used in oral contraceptives, affects hERG function and blockade by drugs. Supratherapeutic concentrations of EE2 did not alter amplitudes or kinetics of the hERG currents elicited by train pulses at 20 mV (0.1 Hz). On the other hand, EE2 at therapeutic concentrations reduced the degree of hERG current suppression by E-4031. The administration of EE2 followed by E-4031 blockade reversed the current suppression, suggesting that the interaction of EE2 and E-4031 alters hERG at the drug-binding site. The effects of EE2 on hERG blockade raised the possibility that other estrogens, including synthetic estrogens, can alter hERG blockade by drugs that cause QT prolongation and ventricular arrhythmias.

scholarly journals Clenbuterol Attenuates hERG Channel by Promoting the Mature Channel Degradation

2017 ◽  
Vol 36 (4) ◽  
pp. 314-324 ◽  
Author(s):  
Ling Luo ◽  
Peijing Hu ◽  
Changqing Miao ◽  
Aiqun Ma ◽  
Tingzhong Wang
Keyword(s):  
Cell Membrane ◽  
Binding Sites ◽  
Drug Binding ◽  
Herg Channel ◽  
Qtc Interval ◽  
Dependent Manner ◽  
Qtc Prolongation ◽  
Herg Current ◽  
Channel Degradation ◽  
Drug Binding Sites

Clenbuterol, a β2-selective adrenergic receptor agonist, is illicitly used in weight loss and performance enhancement and animal production. Increasing evidence demonstrates that clenbuterol induces various kinds of arrhythmias and QTc interval prolongation. However, little is known about the underlying mechanism. Most drugs are associated with QTc prolongation through interfering with human ether-a-go-go-related gene (hERG) K+ channels. The present study aims to investigate the effects and underlying mechanisms of clenbuterol on the hERG channel. HEK 293 cells were transfected with wild type and Y652A or F656A mutants of the hERG channel and treated with clenbuterol. The hERG current was recorded using whole-cell patch-clamp technique, and protein level was evaluated by Western blot. We found that clenbuterol decreases the mature form of the hERG protein at the cell membrane in a concentration- and time-dependent manner, without affecting the immature form. Correspondingly, clenbuterol chronic treatment reduced hERG current to a greater extent compared to acute treatment. In the presence of Brefeldin A (BFA), which was used to block hERG channel trafficking to cell membrane, clenbuterol reduced hERG on plasma membrane to a greater extent than BFA alone. In addition, the hERG channel’s drug binding sites mutant Y652A and F656A abolished clenbuterol-mediated hERG reduction and current blockade. In conclusion, clenbuterol reduces hERG channel expression and current by promoting the channel degradation. The effect of clenbuterol on the hERG channel is related to the drug-binding sites, Tyr-652 and Phe-656, located on the S6 domain. This biophysical mechanism may underlie clenbuterol-induced QTc prolongation or arrhythmia.

scholarly journals High Glucose Represses hERG K+ Channel Expression through Trafficking Inhibition

2015 ◽  
Vol 37 (1) ◽  
pp. 284-296 ◽  
Author(s):  
Yuan-Qi Shi ◽  
Meng Yan ◽  
Li-Rong Liu ◽  
Xiao Zhang ◽  
Xue Wang ◽  
...  
Keyword(s):  
Western Blot ◽  
High Glucose ◽  
Qt Prolongation ◽  
Herg Channel ◽  
K Channel ◽  
Delayed Rectifier ◽  
Patch Clamp Technique ◽  
Down Regulation ◽  
Channel Trafficking ◽  
Herg Current

Background/Aims: Abnormal QT prolongation is the most prominent cardiac electrical disturbance in patients with diabetes mellitus (DM). It is well known that the human ether-ago-go-related gene (hERG) controls the rapid delayed rectifier K+ current (IKr) in cardiac cells. The expression of the hERG channel is severely down-regulated in diabetic hearts, and this down-regulation is a critical contributor to the slowing of repolarization and QT prolongation. However, the intracellular mechanisms underlying the diabetes-induced hERG deficiency remain unknown. Methods: The expression of the hERG channel was assessed via western blot analysis, and the hERG current was detected with a patch-clamp technique. Results: The results of our study revealed that the expression of the hERG protein and the hERG current were substantially decreased in high-glucose-treated hERG-HEK cells. Moreover, we demonstrated that the high-glucose-mediated damage to the hERG channel depended on the down-regulation of protein levels but not the alteration of channel kinetics. These discoveries indicated that high glucose likely disrupted hERG channel trafficking. From the western blot and immunoprecipitation analyses, we found that high glucose induced trafficking inhibition through an effect on the expression of Hsp90 and its interaction with hERG. Furthermore, the high-glucose-induced inhibition of hERG channel trafficking could activate the unfolded protein response (UPR) by up-regulating the expression levels of activating transcription factor-6 (ATF-6) and the ER chaperone protein calnexin. In addition, we demonstrated that 100 nM insulin up-regulated the expression of the hERG channel and rescued the hERG channel repression caused by high glucose. Conclusion: The results of our study provide the first evidence of a high-glucose-induced hERG channel deficiency resulting from the inhibition of channel trafficking. Furthermore, insulin promotes the expression of the hERG channel and ameliorates the high-glucose-induced inhibition of the hERG channel.

scholarly journals Physicochemical Features of the hERG Channel Drug Binding Site

2003 ◽  
Vol 279 (11) ◽  
pp. 10120-10127 ◽  
Author(s):  
David Fernandez ◽  
Azad Ghanta ◽  
Gregory W. Kauffman ◽  
Michael C. Sanguinetti
Keyword(s):  
Binding Site ◽  
Drug Binding ◽  
Herg Channel ◽  
Drug Binding Site ◽  
Physicochemical Features

scholarly journals Kinetics of drug–ribosome interactions defines the cidality of macrolide antibiotics

2017 ◽  
Vol 114 (52) ◽  
pp. 13673-13678 ◽  
Author(s):  
Maxim S. Svetlov ◽  
Nora Vázquez-Laslop ◽  
Alexander S. Mankin
Keyword(s):  
Ribosomal Subunit ◽  
Drug Binding ◽  
Side Chain ◽  
Alkyl Aryl ◽  
Cell Growth Arrest ◽  
Drug Binding Site ◽  
Exit Tunnel ◽  
Critical Components ◽  
Slow Dissociation ◽  
Kinetics Of

Antibiotics can cause dormancy (bacteriostasis) or induce death (cidality) of the targeted bacteria. The bactericidal capacity is one of the most important properties of antibacterial agents. However, the understanding of the fundamental differences in the mode of action of bacteriostatic or bactericidal antibiotics, especially those belonging to the same chemical class, is very rudimentary. Here, by examining the activity and binding properties of chemically distinct macrolide inhibitors of translation, we have identified a key difference in their interaction with the ribosome, which correlates with their ability to cause cell death. While bacteriostatic and bactericidal macrolides bind in the nascent peptide exit tunnel of the large ribosomal subunit with comparable affinities, the bactericidal antibiotics dissociate from the ribosome with significantly slower rates. The sluggish dissociation of bactericidal macrolides correlates with the presence in their structure of an extended alkyl-aryl side chain, which establishes idiosyncratic interactions with the ribosomal RNA. Mutations or chemical alterations of the rRNA nucleotides in the drug binding site can protect cells from macrolide-induced killing, even with inhibitor concentrations that significantly exceed those required for cell growth arrest. We propose that the increased translation downtime due to slow dissociation of the antibiotic may damage cells beyond the point where growth can be reinitiated upon the removal of the drug due to depletion of critical components of the gene-expression pathway.

Drug Repurposing Studies Targeting SARS-nCoV2: An Ensemble Docking Approach on Drug Target 3C-like Protease (3CLpro)

2020 ◽  
Author(s):  
Shruti Koulgi ◽  
Vinod Jani ◽  
Mallikarjunachari Uppuladinne ◽  
Uddhavesh Sonavane ◽  
Asheet Kumar Nath ◽  
...  
Keyword(s):  
Drug Repurposing ◽  
Drug Binding ◽  
Ensemble Docking ◽  
Drug Molecules ◽  
Drug Binding Site ◽  
Main Protease ◽  
Docking Approach ◽  
Novel Coronavirus ◽  
Markov State Modeling ◽  
Viral Polyprotein

<p>The COVID-19 pandemic has been responsible for several deaths worldwide. The causative agent behind this disease is the Severe Acute Respiratory Syndrome – novel Coronavirus 2 (SARS-nCoV2). SARS-nCoV2 belongs to the category of RNA viruses. The main protease, responsible for the cleavage of the viral polyprotein is considered as one of the hot targets for treating COVID-19. Earlier reports suggest the use of HIV anti-viral drugs for targeting the main protease of SARS-CoV, which caused SARS in the year 2002-03. Hence, drug repurposing approach may prove to be useful in targeting the main protease of SARS-nCoV2. The high-resolution crystal structure of 3CL<sup>pro</sup> (main protease) of SARS-nCoV2 (PDB ID: 6LU7) was used as the target. The Food and Drug Administration (FDA) approved and SWEETLEAD database of drug molecules were screened. The apo form of the main protease was simulated for a cumulative of 150 ns and 10 μs open source simulation data was used, to obtain conformations for ensemble docking. The representative structures for docking were selected using RMSD-based clustering and Markov State Modeling analysis. This ensemble docking approach for main protease helped in exploring the conformational variation in the drug binding site of the main protease leading to efficient binding of more relevant drug molecules. The drugs obtained as best hits from the ensemble docking possessed anti-bacterial and anti-viral properties. Small molecules with these properties may prove to be useful to treat symptoms exhibited in COVID-19. This <i>in-silico</i> ensemble docking approach would support identification of potential candidates for repurposing against COVID-19.</p>

Abstract 14311: Qt Interval Correlation Between Telemetry and 12-lead Electrocardiogram

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Mohamed Farhan Nasser ◽  
Ahmad Jabri ◽  
Saima Karim ◽  
Elizabeth Kaufman
Keyword(s):  
Qt Interval ◽  
Ventricular Arrhythmias ◽  
Qt Prolongation ◽  
T Wave ◽  
Qt Intervals ◽  
Increased Risk ◽  
Tangent Method ◽  
Wave Morphology ◽  
Monitoring Service ◽  
Inpatient Units

Introduction: QT prolongation is associated with increased risk of ventricular arrhythmias.As many patients with COVID19 may be started on QT prolonging drugs, measuring and monitoring QT is imperative to prevent fatal ventricular arrhythmias. However, we need to limit exposure of staff to patients with confirmed COVID19 and judiciously use personal protective equipment. Thus, it is important to find alternatives to doing frequent 12-lead ECGs. Hypothesis: We hypothesize that the QT interval measured from telemetry is similar to the QT interval on 12-lead ECG. Methods: Telemetry recordings and 12-lead ECGs were obtained from 15 patients at the same time and identical heart rates. Patients were from two different inpatient units with the same telemetry monitoring service. QT intervals were measured manually using calipers with the tangent method, excluding U waves. Telemetry recordings included lead I and II or a precordial lead. QT from telemetry was compared to the corresponding leads and to the longest QT on the 12-lead ECG. In cases of atrial fibrillation (AF), the QT from all the complexes was averaged. Results: Of 15 patients, 2 were in AF and 2 had RBBB. One patient had abnormal T-wave morphology and QT prolongation (abnormal repolarization). In all patients, QT intervals from the same leads as telemetry matched the QT measured from 12-lead. In 14 of 15 patients, telemetry QT matched the longest QT on the 12-lead ECG. However, in the patient with abnormal repolarization, maximum QT on 12-lead ECG was substantially longer than telemetry QT (Figure 1). Conclusion: When using the same lead, QT intervals were identical on telemetry and 12-lead ECG. However, in the patient with abnormal repolarization, the longest QT on 12-lead ECG was not represented on telemetry. In patients with abnormal repolarization on 12-lead ECG, we recommend serial 12-lead ECGs while on QT-prolonging drugs. Telemetry may suffice as a surrogate for 12-lead ECG to follow QT intervals in most patients.

scholarly journals Psychomotor stimulant effects of α-pyrrolidinovalerophenone (αPVP) enantiomers correlate with drug binding kinetics at the dopamine transporter

2021 ◽  
Author(s):  
Marco Niello ◽  
Spyridon Sideromenos ◽  
Ralph Gradisch ◽  
Ronan O'Shea ◽  
Jakob Schwazer ◽  
...  
Keyword(s):  
Dopamine Transporter ◽  
In Silico ◽  
Drug Binding ◽  
Binding Kinetics ◽  
Irreversible Binding ◽  
Fast Kinetics ◽  
Slow Dissociation ◽  
Kinetics Of

Abstract α-Pyrrolidinovalerophenone (αPVP) is a psychostimulant and drug of abuse associated with severe intoxications in humans. αPVP exerts long-lasting psychostimulant effects, when compared to the classical dopamine transporter (DAT) inhibitor cocaine. Here, we compared the two enantiomeric forms of αPVP, the R- and the S-αPVP, with cocaine using a combination of in silico, in vitro and in vivo approaches. We found that αPVP enantiomers substantially differ from cocaine in their binding kinetics. The two enantiomers differ from each other in their association rates. However, they show similar slow dissociation rates leading to pseudo-irreversible binding kinetics at DAT. The pseudo-irreversible binding kinetics of αPVP is responsible for the observed non-competitive pharmacology and it correlates with persistent psychostimulant effects in mice. Thus, the slow binding kinetics of αPVP enantiomers profoundly differ from the fast kinetics of cocaine both in vitro and in vivo, suggesting drug-binding kinetics as a potential driver of psychostimulant effects in vivo.

scholarly journals Plasmodium falciparum DHODH inhibitor complexes reveal flexible binding site

2014 ◽  
Vol 70 (a1) ◽  
pp. C1793-C1793
Author(s):  
Paul Rowland ◽  
Onkar SINGH ◽  
Leila Ross ◽  
Francisco Gamo ◽  
Maria Lafuente-Monasterio ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Binding Site ◽  
Crystal Structures ◽  
Point Mutations ◽  
Crystal Form ◽  
Drug Binding ◽  
Binding Modes ◽  
Resistance Mutations ◽  
Drug Binding Site

Malaria is a preventable and treatable disease, yet annually there are still hundreds of thousands of malaria-related deaths. The disease is caused by infection with mosquito-borne Plasmodium parasites. With hundreds of millions of cases each year there is a very high potential for drug resistance and this has compromised many existing therapies. One target under investigation is the enzyme dihydroorotate dehydrogenase (DHODH) which catalyses the rate-limiting step of pyrimidine biosynthesis and is an essential enzyme in the malaria parasite. There are currently several Plasmodium-selective DHODH inhibitors under development. To investigate the potential for drug resistance against DHODH inhibitors in vitro resistance selections were carried out using known inhibitors from different structural classes [1]. These studies identified point mutations in the drug binding site which lead to reduced sensitivity to the inhibitors, and in some cases increased sensitivity to a different inhibitor, suggesting a novel combination therapy approach to combat resistance. To help understand the significance of the inhibitor binding site mutations we determined the crystal structures of P. falciparum DHODH in complex with the inhibitors Genz-669178, IDI-6253 and IDI-6273. Co-crystallisation experiments led to a new crystal form in each case. Here we describe the crystal structures, the binding modes of the inhibitors and the great flexibility of the binding site, which is able to adjust to accommodate different inhibitor series. The structural role of the resistance mutations is also discussed.

Sign in / Sign up

Export Citation Format

Share Document