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Structural Optimization of an α-Hairpinin Blocking Potassium Channels KV1.3

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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 KV1.3 channel blocker, with a half-maximal inhibitory concentration (IC50) of ≈150 nM. Molecular dynamics simulation of the Tk-hefu-10–KV1.3 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 KV1.3. 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.

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ACKNOWLEDGMENT

The authors are grateful to Olaf Pongs for providing the plasmid pCI-neo-KV1.3.

Funding

This work was supported by the Russian Science Foundation (project no. 20-44-01015; electrophysiology) and the Russian Foundation for Basic Research (project no. 20-34-90158; peptide production).

Author information

Authors and Affiliations

  1. Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia

    A. M. Gigolaev, V. M. Tabakmakher & A. A. Vassilevski

  2. KU Leuven, Leuven, Belgium

    S. Peigneur & J. Tytgat

  3. Moscow Institute of Physics and Technology (State University), Dolgoprudny, Moscow Region, Russia

    A. A. Vassilevski

Authors
  1. A. M. Gigolaev
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  2. V. M. Tabakmakher
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  3. S. Peigneur
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  4. J. Tytgat
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  5. A. A. Vassilevski
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Contributions

A.M.G. and A.A.V. planned the study. V.M.T. performed molecular modeling. A.M.G. performed biochemical experiments and obtained recombinant peptides. S.P. performed electrophysiological experiments. A.A.V. supervised the biochemical experiments. J.T. supervised the electrophysiological experiments. A.M.G., V.M.T. and A.A.V. wrote the article.

Corresponding author

Correspondence to A. A. Vassilevski.

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COMPLIANCE WITH ETHICAL STANDARDS

This study strictly followed the International Guiding Principles for Biomedical Research Involving Animals of the World Health Organization and the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, 18.III.1986). The study was conducted in accordance with the standards of the Guide for the Care and Use of Laboratory Animals (8th edition, Institute for Laboratory Animal Research). X. laevis frogs were used in Toxicology and Pharmacology, KU Leuven, under the license LA1210239, which was approved by the Ethical Committee for animal experiments of KU Leuven (P186/2019).

CONFLICT OF INTEREST

The authors declare that they have no conflicts of interest.

Additional information

Translated by A. Dyomina

Russian Text © The Author(s), 2023, published in Rossiiskii Fiziologicheskii Zhurnal imeni I.M. Sechenova, 2023, Vol. 109, No. 1, pp. 109–118https://doi.org/10.31857/S0869813923010041.

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Gigolaev, A.M., Tabakmakher, V.M., Peigneur, S. et al. Structural Optimization of an α-Hairpinin Blocking Potassium Channels KV1.3. J Evol Biochem Phys 59, 192–199 (2023). https://doi.org/10.1134/S0022093023010167

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