A method for screening Herg potassium ion channel agonists and toxicity detection

Abstract

The invention relates to a method for screening hERG potassium ion channel agonists and detecting toxicity. Specifically, the present invention firstly relates to a fusion protein, containing as the N-terminus of the fusion protein, between the 1-85 amino acid residues of the N-terminus of the potassium ion channel UNC-103 protein of the nematode ERG family, 75-85 amino acids in length A fragment of residue; hERG or its fragment comprising at least the S1-S6 transmembrane region and the cyclic nucleotide binding domain; and as the fusion protein C-terminal amino acid residue at position 590-829 from the C-terminus of the UNC-103 protein Between bases, a fragment of 220‑240 amino acid residues. It also relates to the polynucleotide sequence encoding the fusion protein, related transgenic nematodes, and related screening methods and applications. The present inventors constructed an in vivo screening method for the first time that can identify compounds that affect hERG intracellular transport, and screen hERG inhibitors or long QT syndrome (LQTS) related channel mutant function correctors, which are hERG toxicants. Physical detection and screening of drugs for the treatment of LQTS provides new ways and methods.

Description

Technical field [0001] The present invention relates to a hERG potassium ion channel agonists and methods of screening for toxicity testing. Background technique [0002] Long QT syndrome (long QT syndrome, LQTS) is a class of diseases caused by cardiac arrhythmia caused by abnormal ion channel, performance prolongation myocardial repolarization, is reflected on an electrocardiogram QT interval prolongation. LQTS easily induced torsades tachycardia (torsades de pointes, TdP), leading to palpitations, fainting, and even sudden death. Congenital and acquired LQTS can be divided into two kinds. Congenital LQTS is caused by a mutation, the mutation occurs mainly in the KCNQ1, KCNH2 (encoding the hERG potassium ion channel) and other ion channel gene SCN5A. hERG channel gene mutations cause about 45% of the total incidence of type II LQTS LQTS (LQTS2). Mainly refers to acquired LQTS prolong the QT interval reversible caused by drugs, studies show that most drugs by inhibiting the hERG...

AI Technical Summary

Problems solved by technology

However, these monitoring instruments are relatively expensive, and generally they can only detect transient hERG channel blockers or agonists that act on the cell membrane, and it is difficult to screen for those compounds that have a longer duration of action and regulate the intracellular transport of hERG channels

More importantly, there is no relevant screening system for corrective compounds that promote the re-membrane of trafficking-deficient mutant hERG channels

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