Natural products modulating the hERG channel: heartaches and hope

Abstract

Covering: 1996-December 2016The human Ether-à-go-go Related Gene (hERG) channel is a voltage-gated potassium channel playing an essential role in the normal electrical activity in the heart. It is involved in the repolarization and termination of action potentials in excitable cardiac cells. Mutations in the hERG gene and hERG channel blockage by small molecules are associated with increased risk of fatal arrhythmias. Several drugs have been withdrawn from the market due to hERG channel-related cardiotoxicity. Moreover, as a result of its notorious ligand promiscuity, this ion channel has emerged as an important antitarget in early drug discovery and development. Surprisingly, the hERG channel blocking profile of natural compounds present in frequently consumed botanicals (i.e. dietary supplements, spices, and herbal medicinal products) is not routinely assessed. This comprehensive review will address these issues and provide a critical compilation of hERG channel data for isolated natural products and extracts over the past two decades (1996-2016). In addition, the review will provide (i) a solid basis for the molecular understanding of the physiological functions of the hERG channel, (ii) the translational potential of in vitro/in vivo results to cardiotoxicity in humans, (iii) approaches for the identification of hERG channel blockers from natural sources, (iv) future perspectives for cardiac safety guidelines and their applications within phytopharmaceuticals and dietary supplements, and (v) novel applications of hERG channel modulation (e.g. as a drug target).

Fig. 1. hERG channel gating. (A) At negative membrane potentials hERG channels are in closed state. The voltage sensor domain (+++) is in the down conformation and the cytoplasmic part of the S5/S6 helix bundle prevents the flow of ions (*). (B) Upon depolarization the channels slowly activate: the voltage sensor domain transitions upwards within the membrane. Via the S4S5 linker this motion is transferred onto the cytoplasmic end of the helix bundle, and the pore allows potassium ions to flow. (C) The channels rapidly undergo inactivation, which is characterized by a collapse of the selectivity filter (*), preventing any further flow of potassium ions.

Fig. 2. Drug block of hERG channel current. (A) Many drugs (red) can bind in the cavity of the hERG channel and block the flow of potassium ions. (B) Drug block can be measured using the patch clamp method and a perfusion system. (C) Example of hERG channel block by cisapride. Normalized peak tail current amplitudes can be measured and plotted against the applied drug concentration to obtain a dose response curve (data collected with a CytoPatch⁴ Instrument).

Fig. 3. Microfractionation and activity profile of an extract with HPLC-PDA chromatogram (lower trace, at 254 nm) and corresponding activity profile (upper trace, % inhibition of hERG channel current) of time-based microfractions. Reproduced from reference Schramm, A. et al. with permission from Georg Thieme Verlag, Stuttgart.

Fig. 4. Natural compounds tested for hERG channel interactions (n = 189). (A) Categorization into alkaloids and non-alkaloids and previously defined activity ranges (strong, moderate, and non-blocker). (B) Chemical property space analysis. The positions are determined by the three principal components (PS1: size, PS2: aromaticity, PS3: lipophilicity), which are summarized from a large number of molecular descriptors. The colors depict strong (red), moderate (green), and non-blockers (blue).

Fig. 5. Matched molecular pairs analysis showing strong (red), moderate (green), and non-blockers (blue). The log P calculations were performed with Marvin (Chemaxon).

Jadel M. Kratz

Ulrike Grienke

Olaf Scheel

Stefan A. Mann

Judith M. Rollinger