Structural Optimization of an α-Hairpinin Blocking Potassium Channels K V 1.3

A. M. Gigolaev; Гиголаев А. М.; V. M. Tabakmakher; Табакмахер В. М.; S. Peigneur; Пеньёр С.; J. Tytgat; Титгат Я.; A. A. Vassilevski; Василевский А. А.

doi:10.31857/S0869813923010041

Structural Optimization of an α-Hairpinin Blocking Potassium Channels K_V1.3

Authors: Gigolaev A.M.¹, Tabakmakher V.M.¹, Peigneur S.², Tytgat J.², Vassilevski A.A.¹^,3
Affiliations:
1. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences
2. KU Leuven
3. Moscow Institute of Physics and Technology (State University)
Issue: Vol 109, No 1 (2023)
Pages: 109-118
Section: EXPERIMENTAL ARTICLES
URL: https://ruspoj.com/0869-8139/article/view/651609
DOI: https://doi.org/10.31857/S0869813923010041
EDN: https://elibrary.ru/IYEAZZ
ID: 651609

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Abstract

Obtaining compounds with specificity for certain isoforms of ion channels is a significant problem of curent physiology and pharmacology. In a series of papers, we have shown that the α-hairpinin fold can serve as a template for the rational design of peptide ligands of potassium channels. Here, we used molecular modeling to optimize the structure of the previously obtained Tk-hefu-10 peptide, a selective K_V1.3 channel blocker, with a half-maximal inhibitory concentration (IC₅₀) of ≈150 nM. Molecular dynamics simulation of the Tk-hefu-10–K_V1.3 complex provided information on the interaction of individual amino acid residues of the peptide and channel, and the analysis of these interactions made it possible to propose amino acid substitutions in the structure of Tk-hefu-10 to increase its affinity. Novel Tk-hefu-12 peptide is a truncated analog of Tk-hefu-10 by one residue with five substitutions; it is characterized by an IC₅₀ value of ≈70 nM against K_V1.3. In addition, there are no methionine residues in the structure of Tk-hefu-12, which makes it possible to obtain Tk-hefu peptides using cyanogen bromide.

Keywords

voltage-gated potassium channel, ligand, blocker, peptide, alpha-hairpinin, recombinant protein

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