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Publication Abstract from PubMed

Among voltage-gated potassium channel (KV) isoforms, KV1.6 is one of the most widespread in the nervous system. However, there are little data concerning its physiological significance, in part due to the scarcity of specific ligands. The known high-affinity ligands of KV1.6 lack selectivity, and conversely, its selective ligands show low affinity. Here, we present a designer peptide with both high affinity and selectivity to KV1.6. Previously, we have demonstrated that KV isoform-selective peptides can be constructed based on the simplistic alpha-hairpinin scaffold, and we obtained a number of artificial Tk-hefu peptides showing selective blockage of KV1.3 in the submicromolar range. We have now proposed amino acid substitutions to enhance their activity. As a result, we have been able to produce Tk-hefu-11 that shows a half-maximal effective concentration (EC50) of approximately 70 nM against KV1.3. Quite surprisingly, Tk-hefu-11 turns out to block KV1.6 with even higher potency, presenting an EC50 of approximately 10 nM. Furthermore, we have solved the peptide structure and used molecular dynamics to investigate the determinants of selective interactions between artificial alpha-hairpinins and KV channels to explain the dramatic increase in KV1.6 affinity. Since KV1.3 is not highly expressed in the nervous system, we hope that Tk-hefu-11 will be useful in studies of KV1.6 and its functions.

Artificial pore blocker acts specifically on voltage-gated potassium channel isoform KV1.6.,Gigolaev AM, Lushpa VA, Pinheiro-Junior EL, Tabakmakher VM, Peigneur S, Ignatova AA, Feofanov AV, Efremov RG, Mineev KS, Tytgat J, Vassilevski AA J Biol Chem. 2022 Sep 7:102467. doi: 10.1016/j.jbc.2022.102467. PMID:36087839^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.