Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation

Borrego, Jesús and Feher, Adam and Jost, Norbert and Panyi, Gyorgy and Varga, Zoltan and Papp, Ferenc (2021) Peptide Inhibitors of Kv1.5: An Option for the Treatment of Atrial Fibrillation. PHARMACEUTICALS, 14 (12). p. 1303. ISSN 1424-8247

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Abstract

Abstract: The human voltage gated potassium channel Kv1.5 that conducts the IKurcurrent is akey determinant of the atrial action potential. Its mutations have been linked to hereditary formsof atrial fibrillation (AF), and the channel is an attractive target for the management of AF. Thedevelopment of IKurblockers to treat AF resulted in small molecule Kv1.5 inhibitors. The selectivityof the blocker for the target channel plays an important role in the potential therapeutic applicationof 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 ofpeptide 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 tosmall molecule inhibitors and thus, generally confer higher selectivity to the peptide blockers. Wefound two peptides in the literature, which inhibited IKur: Ts6 and Osu1. Their affinity and selectivityfor Kv1.5 can be improved by rational drug design in which their amino acid sequences could bemodified in a targeted way guided by in silico docking experiments.

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