Abstract
The human voltage gated potassium channel Kv1.5 that conducts the IKur current is a key determinant of the atrial action potential. Its mutations have been linked to hereditary forms of atrial fibrillation (AF), and the channel is an attractive target for the management of AF. The development of IKur blockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivity of the blocker for the target channel plays an important role in the potential therapeutic application of the drug candidate: the higher the selectivity, the lower the risk of side effects. In this respect, small molecule inhibitors of Kv1.5 are compromised due to their limited selectivity. A wide range of peptide toxins from venomous animals are targeting ion channels, including mammalian channels. These peptides usually have a much larger interacting surface with the ion channel compared to small molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. We found two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivity for Kv1.5 can be improved by rational drug design in which their amino acid sequences could be modified in a targeted way guided by in silico docking experiments.
Highlights
Ion channels are transmembrane proteins, which form a pore in the cell membrane for ions to pass through
The technology to make peptides more selective for a given ion channel is known, along with the computer modelling to aid design, and there are excellent tools to test the efficacy of the peptides
The selectivity of ion channel inhibitors is extremely important for future therapeutic application in order to reduce the unwanted side effects—the higher the selectivity, the lower the risk of side effects
Summary
Ion channels are transmembrane proteins, which form a pore in the cell membrane for ions to pass through. Voltage-gated ion channels (VGICs) form one of the largest groups. These ion channels are involved in a great variety of cellular functions, such as generation of action potentials (AP) in excitable cells or activation in numerous non-excitable cell types, such as lymphocytes and tumor cells. The discovery of voltage-sensing phosphatase (VSP) and the voltage-activated proton channel (Hv1). Revealed that the VSD can exist independently from the ion-conducting pore [5,6,7]. Pharmaceuticals 2021, 14, 1303 voltage-sensing phosphatase (VSP) and the voltage-activated proton channel (Hv1) revealed that the VSD can exist independently from the ion-conducting pore [5,6,7]
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