AI Article Synopsis
- * A study examined 32 plant-derived alkaloids and two semi-synthetic compounds, using an automated assay to assess their effects on the hERG channel.
- * Several alkaloids, including protopine and reserpine, were found to significantly reduce hERG current by at least 50%, indicating a potential toxicity risk associated with these common plant compounds.
Article Abstract
Inhibition of the cardiac human ether-a-go-go-related gene channel is a problematic off-target pharmacological activity and, hence, a major safety liability in clinical practice. Several non-cardiac drugs have been restricted in their use, or even removed from the market due to this potentially fatal adverse effect. Comparatively little is known about the human ether-a-go-go-related gene inhibitory potential of plant-derived compounds. In the course of an ongoing human ether-a-go-go-related gene in vitro study, a total of 32 structurally diverse alkaloids of plant origin as well as two semi-synthetically obtained protoberberine derivatives were screened by means of an automated Xenopus oocyte assay. Protopine, (+)-bulbocapnine, (+)-N-methyllaurotetanine, (+)-boldine, (+)-chelidonine, (+)-corynoline, reserpine, and yohimbine reduced the human ether-a-go-go-related gene current by ≥ 50% at 100 µM, and were submitted to concentration-response experiments. Our data show that some widely occurring plant-derived alkaloids carry a potential risk for human ether-a-go-go-related gene toxicity.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1055/s-0034-1368590 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
AttenhERG: a reliable and interpretable graph neural network framework for predicting hERG channel blockers.
J Cheminform
December 2024
Insilico Medicine Shanghai Ltd, Suite 901, Tower C, Changtai Plaza, 2889 Jinke Road, Pudong New District, Shanghai, 201203, China.
Cardiotoxicity, particularly drug-induced arrhythmias, poses a significant challenge in drug development, highlighting the importance of early-stage prediction of human ether-a-go-go-related gene (hERG) toxicity. hERG encodes the pore-forming subunit of the cardiac potassium channel. Traditional methods are both costly and time-intensive, necessitating the development of computational approaches.
View Article and Find Full Text PDFDiscovery of Thiochroman Derivatives as Potent, Oral Selective Estrogen Receptor Degraders and Antagonists for the Treatment of Endocrine-Resistant Breast Cancer.
J Med Chem
December 2024
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
Selective estrogen receptor degraders (SERDs) deplete the ER signaling pathway via antagonism and degradation of ERα and represent a promising strategy to tackle endocrine resistance. Here, we report a new class of SERDs by pharmacological evolution of a selective estrogen receptor modulator, lasofoxifene. The structure-activity relationship study and efforts to circumvent the issue of human ether-a-go-go-related gene led to the identification of compounds .
View Article and Find Full Text PDFChelerythrine triggers the prolongation of QT interval and induces cardiotoxicity by promoting the degradation of hERG channels.
J Biol Chem
November 2024
Department of Pharmacology, College of Pharmacy, Harbin Medical University, Harbin, Heilongjiang Province, China. Electronic address:
Article Synopsis
- Cardiotoxicity during drug treatment is a significant concern, especially regarding the role of cardiac hERG channels in the heart's action potential repolarization.
- Chelerythrine shows promise as an anti-cancer agent but its safety profile, particularly concerning cardiac effects, is not well understood.
- This study finds that Chelerythrine can prolong the QT interval and action potential duration, potentially increasing the risk of cardiac toxicity through enhanced degradation of hERG channels via ubiquitination and lysosomal pathways under hypoxic conditions.
Stereoselective block of the hERG potassium channel by the Class Ia antiarrhythmic drug disopyramide.
Cell Mol Life Sci
November 2024
School of Physiology, Pharmacology and Neuroscience, Biomedical Sciences Building, University of Bristol, University Walk, Bristol, BS8 1TD, UK.
Article Synopsis
- Potassium channels from the human hERG gene are affected by various drugs, and this study specifically investigates the effects of chiral disopyramide, a Class Ia antiarrhythmic, on hERG currents in HEK 293 cells.* -
- The findings show that the S(+) enantiomer of disopyramide is more potent at inhibiting hERG current compared to the R(-) form, with IC values of 3.9 µM and 12.9 µM respectively, and certain mutations in hERG alter these effects.* -
- Molecular simulations indicate that the S(+) form binds more effectively to specific residues in the hERG channel, while the R(-)
Development of an efficient NUPR1 inhibitor with anticancer activity.
Sci Rep
November 2024
Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR7258, Aix Marseille Université and Institut Paoli Calmettes, Parc Scientifique etTechnologique de Luminy, Equipe labéliséeLigue Nationale contre le cancer, 163 Avenue de Luminy, 13288, Marseille, France.
Pancreatic cancer is highly lethal and has limited treatment options available. Our team had previously developed ZZW-115, a promising drug candidate that targets the nuclear protein 1 (NUPR1), which is involved in pancreatic cancer development and progression. However, clinical translation of ZZW-115 was hindered due to potential cardiotoxicity caused by its interaction with the human Ether-à-go-go-Related Gene (hERG) potassium channel.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!