Novel venom-derived inhibitors of the human EAG channel, a putative antiepileptic drug target

L Ma; Y K Y Chin; Z Dekan; Volker Herzig; C Y Chow; J Heighway; S W Lam; G J Guillemin; P F Alewood; G F King

doi:10.1016/j.bcp.2018.08.038

Back

Novel venom-derived inhibitors of the human EAG channel, a putative antiepileptic drug target

Journal article

Open access

Peer reviewed

Novel venom-derived inhibitors of the human EAG channel, a putative antiepileptic drug target

L Ma, Y K Y Chin, Z Dekan, Volker Herzig, C Y Chow, J Heighway, S W Lam, G J Guillemin, P F Alewood and G F King

Biochemical Pharmacology, Vol.158, pp.60-72

2018

DOI: https://doi.org/10.1016/j.bcp.2018.08.038

Files and links (2)

pdf

PDF - Author's Accepted Version (Open Access)1.28 MBDownload View

Accepted VersionPDF - Author Accepted Version (Open Access)CC BY-NC-ND V4.0, Open Access

url

https://doi.org/10.1016/j.bcp.2018.08.038View

Published Version

Abstract

Kv10.1

hEAG1

hERG

Ion channel

Epilepsy

Recently, we and other groups revealed that gain-of-function mutations in the human ether Ã go-go voltage-gated potassium channel hEAG1 (Kv10.1) lead to developmental disorders with associated infantile-onset epilepsy. However, the physiological role of hEAG1 in the central nervous system remains elusive. Potent and selective antagonists of hEAG1 are therefore much sought after, both as pharmacological tools for studying the (patho)physiological functions of this enigmatic channel and as potential leads for development of anti-epileptic drugs. Since animal venoms are a rich source of potent ion channel modifiers that have been finely tuned by millions of year of evolution, we screened 108 arachnid venoms for hEAG1 inhibitors using electrophysiology. Two hit peptides (Aa1a and Ap1a) were isolated, sequenced, and chemically synthesised for structure-function studies. Both of these hEAG1 inhibitors are C-terminally amidated peptides containing an inhibitor cystine knot motif, which provides them with exceptional stability in both plasma and cerebrospinal fluid. Aa1a and Ap1a are the most potent peptidic inhibitors of hEAG1 reported to date, and they present a novel mode of action by targeting both the activation and inactivation gating of the channel. These peptides should be useful pharmacological tools for probing hEAG1 function as well as informative leads for the development of novel anti-epileptic drugs.

Details

Title: Novel venom-derived inhibitors of the human EAG channel, a putative antiepileptic drug target
Authors: L Ma (Author) - University of Queensland
Y K Y Chin (Author) - University of Queensland
Z Dekan (Author) - University of Queensland
Volker Herzig (Author) - University of Queensland
C Y Chow (Author) - University of Queensland
J Heighway (Author) - University of Queensland
S W Lam (Author) - University of Queensland
G J Guillemin (Author) - Macquarie University
P F Alewood (Author) - University of Queensland
G F King (Author) - University of Queensland
Publication details: Biochemical Pharmacology, Vol.158, pp.60-72
Publisher: Elsevier Inc.
Date published: 2018
DOI: 10.1016/j.bcp.2018.08.038
ISSN: 0006-2952
Organisation Unit: School of Science and Engineering - Legacy; University of the Sunshine Coast, Queensland; School of Science, Technology and Engineering; Centre for Bioinnovation
Language: English
Record Identifier: 99450975402621
Output Type: Journal article

Metrics

97 File views/ downloads

67 Record Views

17 Times Cited - Web of Science

InCites Highlights

These are selected metrics from InCites Benchmarking & Analytics tool, related to this output

Collaboration types: Domestic collaboration
Web Of Science research areas: Pharmacology & Pharmacy

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

Source: InCites