What is hERG channel inhibition?
The human ether-a-go-go related gene (hERG) encodes the inward rectifying voltage gated potassium channel in the heart (IKr) which is involved in cardiac repolarization. Inhibition of the hERG current causes QT interval prolongation resulting in potentially fatal ventricular tachyarrhythmia called Torsade de Pointes.
What does the hERG channel do?
This ion channel (sometimes simply denoted as ‘hERG’) is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart’s beating.
What is hERG receptor?
The human ether-a-go-go-related gene (hERG) encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel (IKr), which is important for cardiac repolarization. Dysfunction of hERG causes long QT syndrome and sudden death, which occur in patients with cardiac ischemia.
Where is the hERG channel?
The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11. 1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines.
What is a hERG assay?
A hERG (human Ether-a-go-go Related Gene) assay is a laboratory technique that gauges the activity of the hERG channel protein. How does the hERG assay support cardiac studies? hERG activity manifests as the movement of potassium ions through a pore present in the hERG channel protein.
What is the significance of hERG assay & QT prolongation studies?
The hERG and in vivo QT data, combined with the likely indication and the estimated free drug level for efficacy, are put together to assess the risk that the potential drug will prolong QT in man.
What is hERG toxicity?
Abstract. Background: hERG K(+) channels have been recognized as a primary antitarget in safety pharmacology. Their blockade, caused by several drugs with different therapeutic indications, may lead to QT prolongation and, eventually, to potentially fatal arrhythmia, namely torsade de pointes.
What is hERG assay?
A hERG (human Ether-a-go-go Related Gene) assay is a laboratory technique that gauges the activity of the hERG channel protein. hERG activity manifests as the movement of potassium ions through a pore present in the hERG channel protein.
What is hERG liability?
Introduction. The inhibition of the human ether-a-go-go (hERG) ion channel may cause QT interval prolongation, which eventually can result in torsades de pointes (TdP) [1] and even death. Hence cardiotoxicity caused by the inhibition of hERG is a major liability within the drug development process.
How do you prevent hERG inhibition?
Introduction of an aliphatic oxygen near to an amine can significantly reduce HERG binding, as can be seen below this can be ascribed to a reduction on the pKa of the basic nitrogen, but also the hydroxyl serves to reduce the overall lipophilicity.
How can I reduce my hERG activity?
What is hERG IC50?
The ratio of the half-maximum inhibitory concentration of the hERG channel (hERG IC50) to the peak serum concentration of unbound drug (Cmax ) is used during drug development to screen out chemical entities likely to cause TdP.
How does the hERG channel inhibition assay work?
The hERG channel inhibition assay is a highly sensitive measurement which will identify compounds exhibiting cardiotoxicity related to hERG inhibition in vivo. It is important to note, however that not all compounds which inhibit hERG activity in vitro will proceed to cause cardiotoxicity in vivo .
What are the side effects of hERG inhibitors?
All along the drug development process, one of the most frequent adverse side effects, leading to the failure of drugs, is the cardiac arrhythmias. Such failure is mostly related to the capacity of the drug to inhibit the human ether-à-go-go-related gene (hERG) cardiac potassium channel.
Which is a positive control for hERG inhibition?
E-4031, a known hERG inhibitor, is used as a positive control for the experiment. DMSO is included as a negative control. How does in vitro hERG inhibition relate to in vivo cardiotoxicity?
Why do so many drugs fail the hERG test?
Such failure is mostly related to the capacity of the drug to inhibit the human ether-à-go-go-related gene (hERG) cardiac potassium channel. The early identification of hERG inhibition properties of biological active compounds has focused most of attention over the years.