An investigation into consumed South African plant species as potential hERG channel blockers

hERG (human Ether-à-go-go Related Gene) is a gene that encodes the pore-forming α-subunit of a voltage-gated potassium K⁺ channel expressed in the heart and in nervous tissue [1]. It is responsible for channels mediating the 'rapid' delayed rectifier K⁺ current (IKI) which plays a critical role in ventricular repolarisation phase of the cardiac action potential [2].

Mutations in hERG can lead to loss of function, prolong the ventricular action potential and may cause an inherited cardiac arrhythmia, long QT syndrome (LQTS) which is associated with torsade de pointes (TdP), a ventricular arrhythmias that can degenerate into ventricular fibrillation, leading to sudden death [3].

129 South African botanicals, distributed in 48 families were investigated for their potential to block hERG K⁺ channels which afforded 350 plant extracts of both DCM and MeOH. Plant extracts which reduced the peak tail current hERG by ≥30% were considered as positive hERG channel blockers. Ten extracts showed inhibitions between 30 – 60%. The highest inhibition percentage was shown by Gnidia polycephala species.

We have demonstrated that a virtual screening approach (two-microelectrode voltage clamp) was successful in identifying novel hERG blockers. This experimentally validated model represents a valuable predictive tool in the assessment of potentially cardiotoxic consumed natural botanicals.

References:

[1] Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sangunetti MC, Stuhmer W, Wang X. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev 2005; 57: 473 – 508

[2] Hancox JC, McPate MJ, Harch AEL, Zong Y-H. The hERG potassium channel and hERG screening of drugs-induced tirsodes de pointes. Pharmacol Therapeut 2008; 119: 118 – 132

[3] Roden DM, Viswanathan PC. Genetics of acquired long QT syndrome. J Clin Invest 2005; 115: 2025 – 2032